CD-40 targeting compositions and uses thereof

WO2026080887A3PCT designated stage Publication Date: 2026-07-16DIABETES FREE INC
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Patent Information

Authority / Receiving Office
WO · WO
Patent Type
Applications
Current Assignee / Owner
DIABETES FREE INC
Filing Date
2025-10-10
Publication Date
2026-07-16

AI Technical Summary

Technical Problem

Existing antibody-based therapeutics face challenges in enhancing clinical efficacy, particularly in balancing pro-inflammatory and anti-inflammatory immune system functions for treating diseases such as cancer and autoimmune disorders.

Method used

Development of CD-40 targeting polypeptide constructs with specific CDR sequences and functional variants, capable of targeting CD-40, CD-20, BAFF, APRIL, and IFNR, to modulate immune responses effectively.

Benefits of technology

The CD-40 targeting polypeptide constructs provide enhanced therapeutic efficacy in treating autoimmune diseases like systemic lupus erythematosus and multiple sclerosis by modulating immune functions.

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Abstract

Disclosed herein are CD-40 targeting compositions that comprise a CD-40 targeting moiety; and in some embodiments, comprises one or two of a CD-20 targeting moiety, a BAFF targeting moiety, an APRIL targeting moiety, or an IFNR 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.
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Description

Attorney Docket No. 199830-740601CD-40 TARGETING COMPOSITIONS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit under 35 U.S.C. § 119(e) of claims the benefit of U.S. Provisional Application No. 63 / 706,361 filed on October 11, 2024, and U.S. Provisional Application No. 63 / 846,668 filed on July 18, 2025, the entire contents of each of which is incorporated herein by reference.BACKGROUND

[0002] The immune system is involved in the pathogenesis of several diseases, including but not limited to cancer, autoimmune diseases, obesity, 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.BRIEF SUMMARY

[0003] Provided herein are compositions, wherein the compositions target CD-40; and (i) CD-20, (ii) B-cell activating factor (BAFF), (iii) A proliferation-inducing ligand (APRIL), (iv) an interferon receptor (IFNR), (v) a receptor expressed on the surface of a cell, or any combination thereof. The compositions provided herein 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 (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 comprisingAttorney Docket No. 199830-740601TDGDY (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 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.

[0006] 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 (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.

[0007] 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: 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 functionalAttorney Docket No. 199830-740601 variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 110 to SEQ ID NO: 125; and (b) a CD-20 targeting moiety.

[0008] Provided herein are compositions, wherein the compositions comprise: (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 heavy chain variable region, wherein the heavy chain variable region 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 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 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 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; and (b) a CD-20 targeting moiety.

[0009] Provided herein are compositions, wherein the compositions comprise: (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; and (b) a CD-20 targeting moiety.

[0010] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a first CD-40 targeting moiety; (b) a second CD-40 targeting moiety; and (c) a CD-20 targeting moiety, wherein the first CD-40 targeting moiety 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 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 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44 or a functional variant thereof, wherein the functionalAttorney Docket No. 199830-740601 variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34 to SEQ ID NO: 44

[0011] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a first CD-40 targeting moiety; (b) a second CD-40 targeting moiety; and (c) a CD-20 targeting moiety, wherein the first CD-40 targeting moiety comprises a light chain variable region that 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

[0012] Provided herein are compositions, wherein the compositions are for use in treating systemic lupus erythematosus, wherein the compositions comprise: a bispecific polypeptide construct comprising: (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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) a CD-20 targeting moiety, wherein the composition is administered to a subject in need thereof thereby treating systemic lupus erythematosus in the subject.

[0013] Provided herein are compositions, wherein the compositions are for use in treating multiple sclerosis, wherein the composition comprises: a bispecific polypeptide construct comprising: (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 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 any one of SEQ ID NO: 20 to SEQ ID NO: 33;Attorney Docket No. 199830-740601 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) a CD-20 targeting moiety, wherein the composition is administered to a subject in need thereof, thereby treating multiple sclerosis in the subject.

[0014] Provided herein are compositions, wherein the compositions are for use in treating an autoimmune disease, wherein the compositions comprise: a bispecific polypeptide construct comprising: (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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) a CD-20 targeting moiety, wherein the composition is administered to a subject in need thereof, thereby treating the autoimmune disease in the subject.

[0015] 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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44

[0016] 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 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) aAttorney Docket No. 199830-740601CDR2 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) a CD-20 targeting moiety.

[0017] 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 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.

[0018] 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 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; and (b) a CD-20 targeting moiety.

[0019] Provided herein are compositions, wherein the compositions comprise: a polypeptide construct 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 the sequences provided herein.

[0020] 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: 161Attorney Docket No. 199830-740601 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.

[0021] 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.

[0022] 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 (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 BAFF targeting moiety.

[0023] 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: 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; and (b) a BAFF targeting moiety.

[0024] Provided herein are compositions, wherein the compositions comprise: (a) a CD-40 targeting moiety comprising an anti-CD-40 antibody or antibody fragment, wherein the anti-CD-40 antibody orAttorney Docket No. 199830-740601 antibody fragment comprises a heavy chain variable region, wherein the heavy chain variable region comprises: ((i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 14 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 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 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; and (b) a BAFF targeting moiety.

[0025] Provided herein are compositions, wherein the compositions comprise: (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; and (b) a BAFF targeting moiety.

[0026] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a first CD-40 targeting moiety; (b) a second CD-40 targeting moiety; and (c) a BAFF targeting moiety, wherein the first CD-40 targeting moiety comprises a heavy chain variable region that comprises: (i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 14 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: 14; (ii) a CDR2 comprising any one of SEQ ID NO: 20 to SEQ ID NO: 28 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: 28; and (iii) a CDR3 comprising any one of SEQ ID NO: 34 to SEQ ID NO: 39 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: 39

[0027] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a first CD-40 targeting moiety; (b) a second CD-40 targeting moiety; and (c) a BAFF targeting moiety, wherein the first CD-40 targeting moiety comprises a light chain variable region that comprises: (i) aAttorney Docket No. 199830-740601CDR1 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

[0028] Provided herein are compositions, wherein the compositions are for use in treating systemic lupus erythematosus, wherein the compositions comprise: a bispecific polypeptide construct comprising: (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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) a BAFF targeting moiety, wherein the composition is administered to a subject in need thereof thereby treating systemic lupus erythematosus in the subject.

[0029] Provided herein are compositions, wherein the compositions are for use in treating multiple sclerosis, wherein the composition comprises: a bispecific polypeptide construct comprising: (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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) a BAFF targeting moiety, wherein the composition is administered to a subject in need thereof, thereby treating multiple sclerosis in the subject.Attorney Docket No. 199830-740601

[0030] Provided herein are compositions, wherein the compositions are for use in treating an autoimmune disease, wherein the compositions comprise: a bispecific polypeptide construct comprising: (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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) a BAFF targeting moiety, wherein the composition is administered to a subject in need thereof, thereby treating the autoimmune disease in the subject.

[0031] 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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) a BAFF targeting moiety.

[0032] 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 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; and (b) a BAFF targeting moiety.Attorney Docket No. 199830-740601

[0033] Provided herein are compositions, wherein the compositions comprise: a polypeptide construct 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; and any additional sequence provided herein.

[0034] 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; and a BAFF 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: 205 to SEQ ID NO: 248.

[0035] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a CD-40 targeting moiety; and A proliferation-inducing ligand (APRIL)-targeting moiety. Further provided herein are polypeptide constructs, wherein the polypeptide constructs further comprise a BAFF -targeting moiety, an interferon receptor-targeting moiety, a CD-20 targeting moiety, or any combination thereof.

[0036] 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 (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) an APRIL targeting moiety.

[0037] 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: 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 toAttorney Docket No. 199830-740601SEQ 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; and (b) an APRIL targeting moiety.

[0038] Provided herein are compositions, wherein the compositions comprise: (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 heavy chain variable region, wherein the heavy chain variable region comprises: (i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 14 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: 14; (i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 14 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: 14; (ii) a CDR2 comprising any one of SEQ ID NO: 20 to SEQ ID NO: 28 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: 28; and (iii) a CDR3 comprising any one of SEQ ID NO: 34 to SEQ ID NO: 39 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: 39; and (b) an APRIL targeting moiety.

[0039] Provided herein are compositions, wherein the compositions comprise: (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; and (b) an APRIL targeting moiety.

[0040] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a first CD-40 targeting moiety; (b) a second CD-40 targeting moiety; and (c) an APRIL targeting moiety, wherein the first CD-40 targeting moiety comprises a heavy chain variable region that comprises: (i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 14 or a functionalAttorney Docket No. 199830-740601 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: 14; (ii) a CDR2 comprising any one of SEQ ID NO: 20 to SEQ ID NO: 28 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: 28; and (iii) a CDR3 comprising any one of SEQ ID NO: 34 to SEQ ID NO: 39 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: 39

[0041] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a first CD-40 targeting moiety; (b) a second CD-40 targeting moiety; and (c) an APRIL targeting moiety, wherein the first CD-40 targeting moiety comprises a light chain variable region that 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

[0042] Provided herein are compositions, wherein the compositions are for use in treating systemic lupus erythematosus, wherein the compositions comprise: a bispecific polypeptide construct comprising: (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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) a CD-20 targeting moiety, wherein the composition is administered to a subject in need thereof thereby treating systemic lupus erythematosus in the subject.

[0043] Provided herein are compositions, wherein the compositions are for use in treating multiple sclerosis, wherein the composition comprises: a bispecific polypeptide construct comprising: (a) a CD- 40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising: (i) aAttorney Docket No. 199830-740601CDR1 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) an APRIL targeting moiety, wherein the composition is administered to a subject in need thereof, thereby treating multiple sclerosis in the subject.

[0044] Provided herein are compositions, wherein the compositions are for use in treating an autoimmune disease, wherein the compositions comprise: a bispecific polypeptide construct comprising: (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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) an APRIL targeting moiety, wherein the composition is administered to a subject in need thereof, thereby treating the autoimmune disease in the subject.

[0045] 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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) an APRIL targeting moiety.Attorney Docket No. 199830-740601

[0046] 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 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; and (b) an APRIL targeting moiety.

[0047] Provided herein are compositions, wherein the compositions comprise: a polypeptide construct 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.

[0048] 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.

[0049] 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 BAFF 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: 202 to SEQ ID NO: 248

[0050] 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%Attorney Docket No. 199830-740601 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 an APRIL 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: 250 to SEQ ID NO: 272

[0051] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a CD-40 targeting moiety; and (b) an interferon receptor-targeting moiety. Further provided herein are polypeptide constructs, wherein the polypeptide constructs further comprise a BAFF-targeting moiety, an APRIL-targeting moiety, a CD-20 targeting moiety, or any combination thereof.

[0052] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a CD-40 targeting moiety; and (b) an interferon alpha / beta receptor alpha chain (IFNR) targeting moiety.

[0053] 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) an IFNR targeting moiety.

[0054] 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: 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 functionalAttorney Docket No. 199830-740601 variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 110 to SEQ ID NO: 125; and (b) an IFNR targeting moiety.

[0055] Provided herein are compositions, wherein the compositions comprise: (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 heavy chain variable region, wherein the heavy chain variable region comprises: (i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 14 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: 14; (ii) a CDR2 comprising any one of SEQ ID NO: 20 to SEQ ID NO: 28 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: 28; and (iii) a CDR3 comprising any one of SEQ ID NO: 34 to SEQ ID NO: 39 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: 39; and (b) an IFNR targeting moiety.

[0056] Provided herein are compositions, wherein the compositions comprise: (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; and (b) an IFNR targeting moiety.

[0057] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a first CD-40 targeting moiety; (b) a second CD-40 targeting moiety; and (c) an IFNR targeting moiety, wherein the first CD-40 targeting moiety comprises a heavy chain variable region that comprises: (i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 14 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: 14; (ii) a CDR2 comprising any one of SEQ ID NO: 20 to SEQ ID NO: 28 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: 28; and (iii) a CDR3 comprising any one of SEQ ID NO: 34 to SEQ ID NO: 39 or a functional variant thereof, wherein the functionalAttorney Docket No. 199830-740601 variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34 to SEQ IDNO: 39

[0058] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a first CD-40 targeting moiety; (b) a second CD-40 targeting moiety; and (c) an IFNR targeting moiety, wherein the first CD-40 targeting moiety comprises a light chain variable region that 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

[0059] Provided herein are compositions, wherein the compositions are for use in treating systemic lupus erythematosus, wherein the compositions comprise: a bispecific polypeptide construct comprising: (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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) a CD-20 targeting moiety, wherein the composition is administered to a subject in need thereof thereby treating systemic lupus erythematosus in the subject.

[0060] Provided herein are compositions, wherein the compositions are for use in treating multiple sclerosis, wherein the composition comprises: a bispecific polypeptide construct comprising: (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 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 any one of SEQ ID NO: 20 to SEQ ID NO: 33;Attorney Docket No. 199830-740601 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) an IFNR targeting moiety, wherein the composition is administered to a subject in need thereof, thereby treating multiple sclerosis in the subject.

[0061] Provided herein are compositions, wherein the compositions are for use in treating an autoimmune disease, wherein the compositions comprise: a bispecific polypeptide construct comprising: (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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) an IFNR targeting moiety, wherein the composition is administered to a subject in need thereof, thereby treating the autoimmune disease in the subject.

[0062] 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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) an IFNR targeting moiety.

[0063] 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 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 comprisingAttorney Docket No. 199830-740601 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; and (b) an IFNR targeting moiety.

[0064] 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: 1 to SEQ ID NO: 272.

[0065] Provided herein are nucleic acids, wherein the nucleic acids encode for a polypeptide construct provided herein, a bispecific polypeptide construct provided herein, a composition provided herein, or an engineered polypeptide provided herein.

[0066] Provided herein are vectors, wherein the vectors comprise a nucleic acid provided herein.

[0067] Provided herein are cells, wherein the cells comprise a nucleic acid of provided herein or a vector provided herein.

[0068] Provided herein are pharmaceutical compositions, wherein the pharmaceutical compositions comprise: a polypeptide construct provided herein, a bispecific polypeptide construct provided herein, a composition provided herein, an engineered polypeptide provided herein, a nucleic acid provided herein, a vector provided herein, a cell provided herein, or an injectable formulation provided herein; and a pharmaceutically acceptable carrier, excipient, or diluent.

[0069] Provided herein are drug delivery devices, wherein the drug delivery devices comprise: a reservoir comprising a pharmaceutical composition provided herein.

[0070] 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 pharmaceutical composition provided herein, thereby treating the disease in the subject.

[0071] 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 pharmaceutical composition provided herein, thereby inducing immune tolerance in the subject.

[0072] Provided herein are methods of reducing inflammation in a subject, wherein the methods comprise: administering to the subject a therapeutically effective amount of a pharmaceutical composition provided herein, thereby reducing inflammation in the subject relative to a level of inflammation in the subject prior to administering the pharmaceutical composition.INCORPORATION BY REFERENCEAttorney Docket No. 199830-740601

[0073] 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

[0074] 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:

[0075] FIGURE 1 shows a schematic representation of a CD-40 targeting moiety provided herein.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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, Rituxan, 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:Attorney Docket No. 199830-740601Time; 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.

[0081] 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.

[0082] 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, Kesimpta 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.

[0083] 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 followingAttorney Docket No. 199830-740601 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] FIGURES 13A-13B show graphs showing concentration of blood conventional dendritic cells in peripheral blood in response to different antibody treatments. FIG. 13A shows a 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.

[0088] 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 aAttorney Docket No. 199830-740601 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.

[0089] 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.

[0090] 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 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: cells per microliter.

[0091] 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,Attorney Docket No. 199830-740601Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X- axis: Time Y-axis: nanogram per milliliter.

[0092] 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 WSUDLCL2 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.

[0093] 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.

[0094] 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).

[0095] FIGURE 21 shows a graph showing antibody-dependent cell-mediated cytotoxicity (ADCC) ofDFI105, abispecific DFI105 / ofatumumab antibody (Crossmab 2), abispecific DFI105 / ofatumumab FabScfvl, and a human IgG4 isotype control in Raji / PBMCs. X-axis: concentration (nM); Y-axis: % cytotoxicity.

[0096] 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.

[0097] 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.

[0098] 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.Attorney Docket No. 199830-740601

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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, FabScfvl, IgG4 isotype, DFI105 / ofatumumab Crossmab2, DFI105 / ofatumumab FabScfv, rituximab, ofatumumab, and IgGl isotype. X-axis: concentration (nM); Y-axis: cell numbers.

[0107] 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.

[0108] 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,Attorney Docket No. 199830-740601IgG4 isotype, DFI105 / ofatumumab Crossmab2, DFI105 / ofatumumab FabScfv, rituximab, ofatumumab, and IgGl isotype. X-axis: concentration (nM); Y-axis: cell numbers.

[0109] 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.

[0110] 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_DFI105- FAB_Ofatumumab-ds- ScFv_DFI105 VH.VL; WBP72458 3 - CrossVHVL_DFH05- FAB Ofatumumab; WBP72458 1 - Diabody_DFI105- FAB Ofatumumab; scFv(Ofat / DFI); Crossmab(RTX / DFI); DFI105; and WBP72458 10 - FAB_Ofatumumab-ds- ScFv_DFI105 VL.VH; DFI105. X-axis: Concentration (ng / ml); Y-axis: % inhibition.

[0111] 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.DETAILED DESCRIPTION OF THE INVENTION

[0112] 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.

[0113] 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 into 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 describedAttorney Docket No. 199830-740601 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.

[0114] 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 receptor-targeting moiety is a type 1 interferon receptor subunit (IFNARl)-targeting moiety. In some embodiments, the interferon receptortargeting 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).

[0115] Provided herein are (1) CD-40 targeting moi eties; (2) CD-20 targeting moi eties; (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

[0116] 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.

[0117] 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.”

[0118] 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 specifically 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.Attorney Docket No. 199830-740601

[0119] 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.

[0120] 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.

[0121] 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.

[0122] The term “effective amount” or “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired effect.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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 ofAttorney Docket No. 199830-740601 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, NTH 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).

[0127] 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 sub-domains are called “hypervariable regions” or “complementarity determining regions” (CDRs). The more conserved (i.e., nonhypervariable) portions of the variable domains are called the “framework” regions (FRM or FR) and provide a scaffold for the six CDRs in three-dimensional space to form an antigen-binding surface.

[0128] 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 ofAttorney Docket No. 199830-740601 the class IgA, IgD, IgE, IgG, and IgM. These classes are also designated a, 5, s, y, and p, respectively. Several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0129] 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).

[0130] The terms “VHH” or “nanobody” and their grammatical equivalents are used interchangeably herein to refer to a single variable domain heavy chain antibody.

[0131] 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.

[0132] 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, 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.Attorney Docket No. 199830-740601

[0133] 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.

[0134] 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 Tar getins Heavy Chain Compositions

[0135] 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.

[0136] 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 at 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.

[0137] 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.Attorney Docket No. 199830-740601Table 1. CD-40 Targeting Moiety Heavy Chain CDR1.

[0138] 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 that 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.Attorney Docket No. 199830-740601

[0139] 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.

[0140] 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. 199830-740601

[0141] 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.

[0142] 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

[0143] 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. 199830-740601

[0144] 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.

[0145] 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

[0146] 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. 199830-740601Attorney Docket No. 199830-740601bold text: CDR sequences X = any amino acid

[0147] 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: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLS S VVTVPS S SLGTKT YTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPP KPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCAttorney Docket No. 199830-740601LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVM HEALHNHYTQKSLSLSLG (SEQ ID NO: 62).

[0148] 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. 199830-740601Attorney Docket No. 199830-740601Attorney Docket No. 199830-740601underlined font: variable region

[0149] 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); MDMRVPAQLLGLLLLWLRGARCAttorney Docket No. 199830-740601(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.

[0150] 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% 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:

[0151] A / KHZIFFZZZZE4APPIPPZNQVQLQESGPGLVKPSETLSITCTVSGFSLSRYSVYWV RQPPGKGLEWMGMMWGGGSTDYSTSLKSRLTISKDTSKSOVSLKMSSLTAADTAVYYCV RTDGDYWGOGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (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 Tar getins Light Chain Compositions

[0152] 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.

[0153] 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.

[0154] 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 comprisesAttorney Docket No. 199830-740601RSSQSLASSQGNTYLH (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. 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.

[0155] 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.

[0156] 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 someAttorney Docket No. 199830-740601 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-40 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

[0157] 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.

[0158] 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 aAttorney Docket No. 199830-740601 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 CDR2 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.

[0159] 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

[0160] 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. Nonlimiting 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. 199830-740601

[0161] 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

[0162] 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.

[0163] 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. 199830-740601Attorney Docket No. 199830-740601bold text: CDRs

[0164] 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.

[0165] 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:RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 138).

[0166] 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. 199830-740601Attorney Docket No. 199830-740601Attorney Docket No. 199830-740601underlined text: light chain variable region

[0167] 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:

[0168] 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.

[0169] 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 RSSQSLAZeSZvGNTYLH, wherein Ze is S, and Z7 is 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 GFSX11SRY, wherein X11 is I, L, or V, preferably wherein X11 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)

[0170] 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:

[0171] Z1Z2Z3Z4TQSPLSLPVTZ5GQPASISCRSSQSLAZ6SZ7GNTYLHWYLQZ8PGQSPRLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGGGTKLEIKR; wherein: Zi, Z2, Z3 and Z4 are ELQL or DIVM; Z5 is L or P; Ze is S or D; Z7 is S or Q; and Zs is R or K (SEQ ID NO: 158).

[0172] In some embodiments, the anti-CD-40 antibody or antigen binding fragment thereof comprises a light chain variable region comprising the sequence:Attorney Docket No. 199830-740601

[0173] Z1Z2Z3Z4TQSPLSLPVTZ5GQPASISCRSSQSLAZ6SZ7GNTYLHWYLQZ8PGQSPRLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGGGTKLEIKR; wherein: Zi, Z2, Z3 and Z4 are ELQL; Z5 is L; and Zs is R (SEQ ID NO: 159).

[0174] In some embodiments, the anti-CD-40 antibody or antigen binding fragment thereof comprises a light chain variable region comprising the sequence:

[0175] Z1Z2Z3Z4TQSPLSLPVTZ5GQPASISCRSSQSLAZ6SZ7GNTYLHWYLQZ8PGQSPRLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGGGTKLEIKR; wherein: Zi, Z2, Z3 and Z4 are DIVM; Z5 is P; Ze is S; Z7 is Q; and Zs is K (SEQ ID NO: 160).

[0176] 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, 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:

[0177] D / ?EPAOZZGZZZZRZ / ?G'A / ?CELQLTQSPLSLPVTLGQPASISCRSSQSLASSQG NTYLHWYLORPGOSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQ STHVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEOLKSGTASVVCLLNNFYPREAKVOWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE C (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

[0178] 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:

[0179] MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTE TECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACE SCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGT NKTDVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEPQEINFPDDLP GSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ (SEQ ID NO: 162).

[0180] 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 targetingAttorney Docket No. 199830-740601 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 amino acid residues or QEPQEINF amino acid residues.

[0181] 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 IgG4 constant region or a mutated human IgGi constant region.

[0182] 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.

[0183] 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.

[0184] 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.Attorney Docket No. 199830-740601

[0185] 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. Nonlimiting 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, the 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.

[0186] 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.

[0187] 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.

[0188] 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.Attorney Docket No. 199830-740601

[0189] 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.

[0190] 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

[0191] 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.

[0192] 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. InAttorney Docket No. 199830-740601 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 vv / ra-differentiated cell. In some embodiments, the CD-20 molecule (also referred to as MS4A1 or membrane spanning 4-domains Al) comprises a sequence that is at least 90% identical to: NCBI Reference No. NP_068769.2 B- lymphocyte antigen CD20 [Homo sapiens

[0193] MTTPRNSVNGTFPAEPMKGPIAMQSGPKPLFRRMSSLVGPTQSFFMRESKTLGAVQ IMNGLFHIALGGLLMIPAGIYAPICVTVWYPLWGGIMYIISGSLLAATEKNSRKCLVKGKMI MNSLSLFAAISGMILSIMDILNIKISHFLKMESLNFIRAHTPYINIYNCEPANPSEKNSPSTQYC YSIQSLFLGILSVMLIFAFFQELVIAGIVENEWKRTCSRPKSNIVLLSAEEKKEQTIEIKEEVVG LTETSSQPKNEEDIEIIPIQEEEEEETETNFPEPPQDQESSPIENDSSP (SEQ ID NO: 163).

[0194] 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 Tar getins Heavy Chain Compositions

[0195] 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.

[0196] 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 200Attorney Docket No. 199830-740601 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 heavy chain having an amino acid sequence that is between about 100 amino acids in length and 450 amino acids in length.

[0197] 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.

[0198] 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

[0199] 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 IDAttorney Docket No. 199830-740601NO: 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 three amino acid substitutions as compared to any one of SEQ ID NO: 164 to SEQ ID NO: 169. In some embodiments,

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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 13.Attorney Docket No. 199830-740601Table 13. CD-20 Targeting Moiety Heavy Chain CDR3 Sequences.

[0204] 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: 178. 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: 178. 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: 178. 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: 178. 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: 178. 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: 178. 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: 178. 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: 178. 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: 178. 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: 178. 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: 178.Attorney Docket No. 199830-740601

[0205] 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: 178. In some embodiments, a CD-20 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: 175 to SEQ ID NO: 178. 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: 178. 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: 178. 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: 178. 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: 178.

[0206] 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:

[0207] EVQLVESGGGLVQPGRSLRLSCAASGFTFNDYAMHWVRQAPGKGLEWVSTISWN SGSIGYADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQS SGL YSLS S VVTVPS S SLGTQT YICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 179).

[0208] 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: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSY NQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTV SAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQAttorney Docket No. 199830-740601VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 180).

[0209] 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: QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGDTD YNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLS S VVTVPS S SLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 181).

[0210] 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: EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGNGDTSY NQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSNSYWYFDVWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 182).

[0211] 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: QAYLQQSGAELVRPGASVKMSCKASGYTFTSYNMHWVKQTPRQGLEWIGGIYPGNGDTSY NQKFKGK ATLT VGKS S ST AYMQLS SLT SED S AVYFC ARYD YNYAMD YWGQGT S VT VS SAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTAttorney Docket No. 199830-740601CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 183).

[0212] 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: QIQLVQSGPVLKQPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINTYTGESTY ADDFKGRFAFSLETFVTTACLQINNLKNEDTATYFCARWGPHTAPYSMDNWGQGTSVTVSS AKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLY TLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFP PKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSAL PIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTC MVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSV VHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 184).

[0213] 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: EVQLVESGGGLVQPGRSLRLSCAASGFTFNDYAMHWVRQAPGKGLEWVSTISWNSGSIGY ADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 185).CD-20 Targeting Light Chain Compositions

[0214] 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.

[0215] 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, at least 200 amino acids in length, at least 250 amino acids in length, at least 300 amino acids in length, at leastAttorney Docket No. 199830-740601350 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.

[0216] 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.

[0217] 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

[0218] 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. 199830-740601

[0219] In some embodiments, the CD-20 targeting moiety comprises a light chain comprising a CDR2 region. Non-limiting examples of light chain CDR2 sequences are provided in Table 15.Table 15. CD-20 Targeting Moiety Light Chain CDR2 Sequences.

[0220] 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

[0221] 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.

[0222] 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.Table 16. CD-20 Targeting Moiety Light Chain CDR3 Sequences.Attorney Docket No. 199830-740601

[0223] 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

[0224] 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:Attorney Docket No. 199830-740601196. In some embodiments, a CD-20 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: 193 to SEQ ID NO: 196

[0225] 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:

[0226] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATG IPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 197).

[0227] 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:

[0228] QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGV PVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 198).

[0229] 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:

[0230] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATG IPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 199).

[0231] 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:

[0232] DIVMTQTPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSN LVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPYTFGGGTKVEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 200).CD-20 tarsetins moiety structure and modificationsAttorney Docket No. 199830-740601

[0233] 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 IgG4 constant region or a mutated human IgGi constant region.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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. Nonlimiting 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, or fragmentation, and conjugatingAttorney Docket No. 199830-740601 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.(5) BAFF targeting moieties

[0242] 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).Attorney Docket No. 199830-740601BAFF 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.

[0243] In some embodiments, the BAFF targeting moi eties 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.

[0244] 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 vztro-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 MDDSTEREQSRLTSCLKKREEMKLKECVSILPRKESPSVRSSKDGKLLAATLLLALLSCCLT VVSFYQVAALQGDLASLRAELQGHHAEKLPAGAGAPKAGLEEAPAVTAGLKIFEPPAPGEG NSSQNSRNKRAVQGPEETVTQDCLQLIADSETPTIQKGSYTFVPWLLSFKRGSALEEKENKIL VKETGYFFIYGQVLYTDKTYAMGHLIQRKKVHVFGDELSLVTLFRCIQNMPETLPNNSCYS AGIAKLEEGDELQLAIPRENAQISLDGDVTFFGALKLL (SEQ ID NO: 201).

[0245] 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, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to: SRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLSCRK EQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELDKTHTCPPCPAPEAEGAP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSRDELTKNAttorney Docket No. 199830-740601QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 202)

[0246] 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:AMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLSCRKEQGKFYDHLLRDCISCA SICGQHPKQCAYFCENKLRSEPKSSDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVF SC S VMHEALHNHYTQKSLS LSPGK (SEQ ID NO: 203).

[0247] 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: SLSCRKEQGEYYDHLLRDCISCASICGQHPKQCADFCENKLRSGSGGGGSEPKSSDKTHTCP PCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 204).

[0248] 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, AUR200, VT-109, APLN-303 (Povetacicept) or an antigen binding fragment thereof; derivatives, variants, or combinations thereof.

[0249] 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.Attorney Docket No. 199830-740601

[0250] 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. 199830-740601Attorney Docket No. 199830-740601BAFF Tarsetins Heavy Chain Compositions

[0251] 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.

[0252] 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, atAttorney Docket No. 199830-740601 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.

[0253] 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 18.Table 18. BAFF Targeting Moiety Heavy Chain CDR1 Sequences.

[0254] 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 some 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

[0255] 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 hereinAttorney Docket No. 199830-740601 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.

[0256] 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.

[0257] 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.

[0258] 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 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 three amino acid substitutions as compared to any one of SEQ ID NO: 229 to SEQ ID NO: 232.

[0259] 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.Attorney Docket No. 199830-740601Table 20. BAFF Targeting Moiety Heavy Chain CDR3 Sequences.

[0260] 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. In 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.

[0261] 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 toAttorney Docket No. 199830-740601 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 Tarsetins Light Chain Compositions

[0262] 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.

[0263] 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.

[0264] In some embodiments, the BAFF targeting moiety comprises a light chain comprising a CDR1 region. Non-limiting examples of light chain CDR1 sequences are provided in Table 21.Table 21. BAFF Targeting Moiety Light Chain CDR1 Sequences.Attorney Docket No. 199830-740601

[0265] 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

[0266] 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.

[0267] 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.Table 22. BAFF Targeting Moiety Light Chain CDR2 Sequences.Attorney Docket No. 199830-740601

[0268] 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

[0269] 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

[0270] 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.

[0271] 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 CDR3 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,Attorney Docket No. 199830-740601 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

[0272] 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: 248.BAFF targeting moiety structure and modi fications

[0273] 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 IgG4 constant region or a mutated human IgGi constant region.

[0274] 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, theAttorney Docket No. 199830-740601BAFF 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.

[0275] 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.

[0276] 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.

[0277] 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. Nonlimiting 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.

[0278] 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 formedAttorney Docket No. 199830-740601 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.

[0279] 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.

[0280] 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.

[0281] 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 ligand 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 MPASSPFLLAPKGPPGNMGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRR EVSRLQGTGGPSQNGEGYPWQSLPEQSSDALEAWENGERSRKRRAVLTQKQKKQHSVLHL VPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQ VVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGT FLGFVKL (SEQ ID NO: 249).Attorney Docket No. 199830-740601

[0282] Provided herein are APRIL targeting moieties that comprise a fusion protein. In some embodiments, the APRIL 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.

[0283] 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.

[0284] 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.Table 24. APRIL-targeting moiety sequences.Attorney Docket No. 199830-740601Attorney Docket No. 199830-740601APRIL Tarsetins Heavy Chain Compositions

[0285] 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.

[0286] 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 a heavy chain having an amino acid sequence that is between about 100 amino acids in length and 450 amino acids in length.

[0287] 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.

[0288] 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. InAttorney Docket No. 199830-740601 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.

[0289] 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.

[0290] 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 26.Table 26. APRIL Targeting Moiety Heavy Chain CDR2 Sequences.

[0291] 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.Attorney Docket No. 199830-740601

[0292] 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.

[0293] 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.

[0294] 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 ID NO: 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 someAttorney Docket No. 199830-740601 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.

[0295] 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 Tar getins Light Chain Compositions

[0296] Provided herein are compositions comprising an APRIL targeting moiety, wherein the APRIL 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.

[0297] 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 someAttorney Docket No. 199830-740601 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.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] 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.Attorney Docket No. 199830-740601

[0302] 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

[0303] 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.

[0304] 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 ID NO: 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 someAttorney Docket No. 199830-740601 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.

[0305] 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 modi fications

[0306] 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 region is a region that is deficient in complement activation, for example, a human IgG4 constant region or a mutated human IgGi constant region.

[0307] 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.Attorney Docket No. 199830-740601

[0308] 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.

[0309] 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.

[0310] 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. Nonlimiting 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 least fifteen, at least sixteen, at least seventeen, at least eighteen, at nineteen, at least twenty, amino acids that are covalently modified.

[0311] 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.

[0312] 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 constantAttorney Docket No. 199830-740601 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.

[0313] 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.

[0314] 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 chain 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.

[0315] 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 someAttorney Docket No. 199830-740601 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

[0316] 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.

[0317] 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 targeting moiety comprises one light chain and two heavy chains. In some embodiments, the IFNR targeting moiety comprises two light chains and two heavy chains.

[0318] 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.

[0319] 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.

[0320] 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. Nonlimiting examples of such modifications include: half-life extending agents, fusing amphipathic helicesAttorney Docket No. 199830-740601 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.

[0321] 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.

[0322] 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 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 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.

[0323] 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.

[0324] 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.

[0325] Provided herein are compositions comprising a polypeptide construct that targets CD-40 and CD-20. In some embodiments, the polypeptide construct is a bispecific polypeptide constructAttorney Docket No. 199830-740601 comprising a CD-40 targeting moiety provided herein and a CD-20 targeting moiety provided herein. In some embodiments, the polypeptide construct is a tetravalent polypeptide construct comprising two CD-40 targeting moieties provided herein and two CD-20 targeting moieties provided herein.

[0326] 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.

[0327] 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), 5 (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 (X), 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.

[0328] 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.Attorney Docket No. 199830-740601

[0329] 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.

[0330] 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 amino 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.

[0331] 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, z.e., the peptides selected from the group consisting of GGGGS, GGGGSGGGGS, SGGGGSGGGG, GGGGS GGGGS GGGG (SEQ ID NO: 273), GSPGSSSSGS, (G4S), (G4S)2, (G4S)3, (G4S)4, GSGSGSGS, GSGSGNGS, GGSGSGSG, GGSGSG, GGSG, GGSGNGSG, GGNGSGSG, GGNGSG, GGGGSGGGGSGGGGS (SEQ ID NO: 274), and GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 275)

[0332] 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 anti-interleukin 6 receptor (IL6R) antibody, an anti-interleukin 6 (IL-6) antibody, an anti-interleukin 1 antibody, an anticomplement 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.Attorney Docket No. 199830-740601

[0333] 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-doxorubicin 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, lulizumabAttorney Docket No. 199830-740601 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, 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.

[0334] 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 anAttorney Docket No. 199830-740601 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.

[0335] 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 a 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.

[0336] 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.

[0337] 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 (N- and 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.

[0338] 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.Attorney Docket No. 199830-740601

[0339] 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.Construct 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 moietyAttorney Docket No. 199830-740601Construct Type Examples• 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 moiety• 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

[0340] 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.

[0341] 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%Attorney Docket No. 199830-740601 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

[0342] 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, a 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 (i.e., expression vectors) encoding the desired polypeptide or antibody.

[0343] 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 E. coli cells, Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (HEK 293) cells, HeLa cells, baby hamster kidney (BHK) 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 NS0 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.

[0344] 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.

[0345] 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 fusionAttorney Docket No. 199830-740601 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] 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 picornaviral 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.

[0351] 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-20Attorney Docket No. 199830-740601 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.

[0352] 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, 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 di glycerides. 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.

[0353] 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.

[0354] 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 byAttorney Docket No. 199830-740601 encapsulation in liposomes. The ultimate dosage form must be sterile, fluid, and stable under the conditions of manufacture and storage.

[0355] 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)); complexing 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).

[0356] 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 asAttorney Docket No. 199830-740601 sodium chloride or dextrose. In some embodiments, the formulation for parenteral administration is citrate-free.

[0357] 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.

[0358] 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 is used in the formulation as a tonicity agent is mannitol.

[0359] 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).

[0360] 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,Attorney Docket No. 199830-740601 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.

[0361] 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.

[0362] 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 for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer's solution, or dextrose solution.

[0363] 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 (multipledose) formulation.

[0364] 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., di saccharides. 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.

[0365] 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.

[0366] 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.Attorney Docket No. 199830-740601

[0367] 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.

[0368] 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 is 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. In some embodiments, the drug delivery devices is an autoinjector.

[0369] An intravenous or subcutaneous drug delivery formulation may be contained in a syringe, pen, or 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.

[0370] 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.

[0371] 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,Attorney Docket No. 199830-740601 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 experimental animals, e.g., ED50 (the dose is therapeutically effective in 50% of the population) and LD50 (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.

[0372] 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.

[0373] 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.

[0374] 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.Attorney Docket No. 199830-740601Alternatively, 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. The 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.

[0375] 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.

[0376] 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.

[0377] 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 firstAttorney Docket No. 199830-740601 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.

[0378] 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.(11) Methods Of Treating a Disease.

[0379] Provided herein are methods of treating a disease in a subject in need thereof. 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 or 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 exampleAttorney Docket No. 199830-740601CD-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.

[0380] In certain embodiments, the polypeptide constructs as disclosed herein comprise an antigenbinding 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, an appendix cancer, a myeloma, a sarcoma, a cancer that primarily affects minors or children, or any combination thereof. In some embodiments, the cancer is a lymphoma. In some embodiments, the lymphoma is a follicular lymphoma, a marginal zone lymphoma, or a mantle cell lymphoma, or a diffuse large B cell lymphoma In some embodiments, the cancer is an acute lymphoblastic leukemia. In some embodiments, the compositions provided herein are used in the treatment of CD40 positive cancers, autoimmune and / or inflammatory disorders. In some embodiments, the compositions provided herein are used in the treatment of CD20 positive cancers, autoimmune and / or inflammatory disorders. In some embodiments, the compositions provided hereinAttorney Docket No. 199830-740601 comprise an CD-40 targeting moiety that binds to a CD-40 protein implicated in an inflammatory disease that is an autoimmune disease.

[0381] 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. In some embodiments, the rheumatoid arthritis is a tumor necrosis factor (TNF) inhibitor non-responding rheumatoid arthritis.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] 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 disease comprises Crohn’s Disease or inflammatory bowel disease. In some embodiments, the disease comprises multiple sclerosis. In someAttorney Docket No. 199830-740601 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.

[0386] 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. 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.

[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 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 separate 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.Attorney Docket No. 199830-740601

[0388] 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.

[0389] 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 some embodiments, the kit comprises an injectable liquid formulation that is allocated into separate units. In some embodiments, the kit comprises an autoinjector.Attorney Docket No. 199830-740601

[0390] 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:

[0391] Provided herein are polypeptide constructs, herein the polypeptide constructs comprise: a CD-40 targeting moiety; and a CD-20 targeting moiety. Further provided herein are polypeptide constructs, wherein the polypeptide constructs comprise two CD-40 targeting moieties. Further provided herein are polypeptide constructs, wherein the polypeptide constructs comprise two CD-20 targeting moieties. Further provided herein are polypeptide constructs, wherein the polypeptide constructs comprise a BAFF-targeting moiety. Further provided herein are polypeptide constructs, wherein the polypeptide constructs comprise an APRIL-targeting moiety. Further provided herein are polypeptide constructs, wherein the polypeptide constructs comprise an interferon receptor-targeting moiety. Further provided herein are polypeptide constructs, wherein the interferon receptor-targeting moiety targets an IFNAR2. Further provided herein are polypeptide constructs, wherein the interferonAttorney Docket No. 199830-740601 receptor-targeting moiety targets an IFNAR1. Further provided herein are compositions, bispecific polypeptide constructs, and polypeptide constructs, wherein 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), relative to (a)-(h) prior to contact with the compositions, bispecific polypeptide constructs, or polypeptide constructs provided herein.

[0392] 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. 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 any one of SEQ ID NO: 45 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 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 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: 64, SEQ ID NO: 68 or SEQ ID NO: 86. FurtherAttorney Docket No. 199830-740601 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: 45 to SEQ ID NO: 56, SEQ ID NO: 63 to SEQ ID NO: 68. 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 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 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:RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (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, an IgG2, an 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 singleAttorney Docket No. 199830-740601 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 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 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. 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: 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. 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 SEQ ID NO: 179 to SEQ ID NO: 185. 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 of 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 IDAttorney Docket No. 199830-740601NO: 193 to SEQ ID NO: 196. Further provided herein are bispecific polypeptide constructs, wherein 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 SEQ ID NO: 197 to SEQ ID NO: 204. 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 polypeptide 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 ...

Claims

1. Attorney Docket No. 199830-740601CLAIMSWHAT IS CLAIMED IS:

1. A bispecific polypeptide construct comprising:(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.

2. The bispecific polypeptide construct of claim 1, 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 any one of SEQ ID NO: 45 to SEQ ID NO: 47.

3. The bispecific polypeptide construct of claim 1, 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: 62.

4. The bispecific polypeptide construct of claim 1, 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: 64, SEQ ID NO: 68 or SEQ ID NO:

865. The bispecific polypeptide construct of claim 1, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a sequence that is at leastAttorney Docket No. 199830-74060180% 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 to SEQ ID NO: 56, SEQ ID NO: 63 to SEQ ID NO:

686. The bispecific polypeptide construct of claim 1, wherein the CD-40 targeting moiety further comprises a light chain.

7. The bispecific polypeptide construct of claim 6, 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: 1108. The bispecific polypeptide construct of claim 6, 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: 1319. The bispecific polypeptide construct of claim 6, 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:RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 138)10. The bispecific polypeptide construct of claim 6, 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: 153Attorney Docket No. 199830-74060111. The bispecific polypeptide construct 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.

12. The bispecific polypeptide construct of claim 11, wherein the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 heavy chain constant region.

13. The bispecific polypeptide construct 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.

14. The bispecific polypeptide construct of claim 1, 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.

15. The bispecific polypeptide construct of claim 1, 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 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: 16916. The bispecific polypeptide construct of claim 1, 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: 17417. The bispecific polypeptide construct of claim 1, 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: 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: 17818. The bispecific polypeptide construct of claim 1, 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 SEQ ID NO: 179 to SEQ ID NO: 185Attorney Docket No. 199830-74060119. The bispecific polypeptide construct of claim 1, 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: 18820. The bispecific polypeptide construct of claim 1, wherein the CD-20 targeting moiety comprises a light chain, wherein the light chain comprises a CDR2 comprising any one of 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: 19221. The bispecific polypeptide construct of claim 1, 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: 19622. The bispecific polypeptide construct of claim 1, wherein 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 SEQ ID NO: 197 to SEQ ID NO: 20423. The bispecific polypeptide construct of claim 1, wherein the bispecific polypeptide construct does not bind to CD-40 ligand (CD40L).

24. The bispecific polypeptide construct of claim 1, wherein the bispecific polypeptide construct further comprises a half-life extension moiety.

25. The bispecific polypeptide construct of claim 24, wherein the half-life extension moiety is an albumin.

26. The bispecific polypeptide construct of claim 1, wherein the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an N-linked glycan.

27. The bispecific polypeptide construct of claim 1, wherein the CD-40 targeting moiety comprises two light chains.

28. The bispecific polypeptide construct of claim 1, wherein the CD-40 targeting moiety comprises two heavy chains.

29. The bispecific polypeptide construct of claim 1, wherein the CD-40 targeting moiety comprises one heavy chain and one light chain.Attorney Docket No. 199830-74060130. The bispecific polypeptide construct of claim 1, wherein the CD-40 targeting moiety comprises two light chains and two heavy chains.

31. The bispecific polypeptide construct of claim 1, wherein the bispecific polypeptide construct comprises an IgA fragment.

32. The bispecific polypeptide construct of claim 1, wherein the bispecific polypeptide construct comprises 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.

33. The bispecific polypeptide construct of claim 32, 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.

34. The bispecific polypeptide construct of claim 33, wherein the import amino acid residue comprises a phenylalanine (F), a tyrosine (Y), or a tryptophan (W).

35. The bispecific polypeptide construct of claim 32, 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 thereof36. The bispecific polypeptide construct of claim 32, 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.

37. A composition comprising:(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 heavy chain variable region, wherein the heavy chain variable region 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 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 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 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; andAttorney Docket No. 199830-740601(b) a CD-20 targeting moiety.

38. A composition comprising:(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; and(b) a CD-20 targeting moiety.

39. The composition of claim 37 or claim 38, 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: 63 to SEQ ID NO: 81.

40. The composition of claim 37 or claim 38, wherein the CD-40 targeting moiety comprises a light chain, 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: 137.

41. The composition of claim 37 or claim 38, 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.

42. The composition of claim 41, wherein the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 heavy chain constant region.

43. The composition of claim 37 or claim 38, 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 fragmentAttorney Docket No. 199830-740601 crystallizable (Fc) domain, a single chain variable fragment, a minibody, a nanobody (VHH), and any combination thereof.

44. The composition of claim 37 or claim 38, wherein the CD-20 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.

45. The composition of claim 37 or claim 38, 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 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: 16946. The composition of claim 37 or claim 38, 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: 17447. The composition of claim 37 or claim 38, 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: 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: 17848. The composition of claim 37 or claim 38, 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 SEQ ID NO: 179 to SEQ ID NO: 18549. The composition of claim 37 or claim 38, wherein the CD-20 targeting moiety comprises a light chain, wherein the light chain comprises a CDR1 comprising any one of SEQ ID NO: 105 to SEQ ID NO: 107 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 105 to SEQ ID NO: 10750. The composition of claim 37 or claim 38, wherein the CD-20 targeting moiety comprises a light chain, wherein the light chain comprises a CDR2 comprising any one SEQ ID NO: 108 to SEQ ID NO: 111 or a functional variant thereof, wherein the functional variantAttorney Docket No. 199830-740601 comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 108 to SEQ ID NO: 11151. The composition of claim 37 or claim 38, wherein the CD-20 targeting moiety comprises a light chain, wherein the light chain comprises a CDR3 comprising any one of SEQ ID NO: 112 to SEQ ID NO: 115 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 112 to SEQ ID NO: 11552. The composition of claim 37 or claim 38, wherein 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 SEQ ID NO: 116, SEQ ID NO: 117, or SEQ ID NO: 11953. The composition of claim 37 or claim 38, wherein the composition does not bind to CD-40 ligand (CD40L).

54. The composition of claim 37 or claim 38, wherein the composition further comprises a half-life extension moiety.

55. The composition of claim 54, wherein the half-life extension moiety is an albumin.

56. The composition of claim 37 or claim 38, wherein the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an N-linked glycan.

57. The composition of claim 37 or claim 38, wherein the CD-40 targeting moiety comprises two light chains.

58. The composition of claim 37 or claim 38, wherein the CD-40 targeting moiety comprises two heavy chains.

59. The composition of claim 37 or claim 38, wherein the CD-40 targeting moiety comprises one heavy chain and one light chain.

60. The composition of claim 37 or claim 38, wherein the CD-40 targeting moiety comprises two light chains and two heavy chains.

61. The composition of claim 37 or claim 38, wherein the CD-40 targeting moiety or the CD-20 targeting moiety comprises an IgA fragment.

62. The composition of claim 37 or claim 38, wherein the CD-40 targeting moiety or the CD-20 targeting moiety comprises a constant domain comprising one or more amino acid substitutions that increase multimerization of the CD-40 targeting moiety and the CD-20 targeting moiety.Attorney Docket No. 199830-74060163. The composition of claim 62, 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 having a larger side chain volume than the original amino acid residue.

64. The composition of claim 63, wherein the import amino acid residue comprises a phenylalanine (F), a tyrosine (Y), or a tryptophan (W).

65. The composition of claim 62, 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 thereof66. The composition of claim 62, 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 comprises a cysteine (C) relative to the original amino acid residue.

67. An engineered polypeptide comprising:(a) a first CD-40 targeting moiety;(b) a second CD-40 targeting moiety; and(c) a CD-20 targeting moiety, wherein the first CD-40 targeting moiety 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 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 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 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.

68. An engineered polypeptide comprising:(a) a first CD-40 targeting moiety;(b) a second CD-40 targeting moiety; and(c) a CD-20 targeting moiety, wherein the first CD-40 targeting moiety comprises a light chain variable region that 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 twoAttorney Docket No. 199830-740601 amino acid substitutions as compared to any one of SEQ ID NO: 47 to SEQ ID NO: 48;(ii) a CDR2 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 SEQ ID NO: 87 to SEQ ID NO: 95; and(iii) a CDR3 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.

69. The engineered polypeptide of claim 67 or claim 68, wherein the engineered polypeptide further comprises one or more linkers.

70. The engineered polypeptide of claim 69, wherein the one or more linkers directly link the first CD-40 targeting moiety; the second CD-40 targeting moiety; and / or the CD-20 targeting moiety.

71. The engineered polypeptide of any one of claims 67 to 70, further comprising an additional antigen binding moiety.

72. The engineered polypeptide of any one of claims 67 to 71, wherein the first CD-40 targeting moiety or the second CD-40 targeting moiety do not bind to CD40L.

73. The engineered polypeptide of any one of claims 67 to 72, wherein the first CD-40 targeting moiety or the second CD-40 targeting moiety comprise an antibody fragment, wherein the antibody fragment comprises a F(ab')2, a Fab, a Fab', a Fv, an scFv, or a VHH.

74. The engineered polypeptide of any one of claims 67 to 73, wherein the CD-20 targeting moiety comprises an antibody fragment, wherein the antibody fragment comprises a F(ab')2, a Fab, a Fab', a Fv, an scFv, or a VHH.

75. The engineered polypeptide of any one of claims 67 to 74, wherein the first CD-40 targeting moiety or the second CD-40 targeting moiety comprise a sequence that is at least 80% identical to any one of SEQ ID NO: 45 to SEQ ID NO: 81, SEQ ID NO: 86, SEQ ID NO: 126 to SEQ ID NO: 153, SEQ ID NO: 158 to SEQ ID NO: 16176. The engineered polypeptide of any one of claims 67 to 75, wherein the first CD-40 targeting moiety or the second CD-40 targeting moiety comprise a sequence that is at least 80% identical to any one of SEQ ID NO: 86 or SEQ ID NO: 131.

77. The engineered polypeptide of any one of claims 67 to 76, wherein the CD-20 targeting moiety comprises sequence that is at least 80% identical to any one of SEQ ID NO: 164 to SEQ ID NO: 20478. A composition comprising:Attorney Docket No. 199830-740601(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: 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 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 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; and(b) a B-cell activating factor (BAFF)-targeting moiety.

79. The composition of claim 78, wherein the BAFF -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.

80. The composition of claim 78 or claim 79, wherein the BAFF-targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR1 comprising any one of SEQ ID NO: 225 to SEQ ID NO: 228 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 225 to SEQ ID NO: 22881. The composition of any one of claims 78 to 80, wherein the BAFF-targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR2 comprising any one of SEQ ID NO: 229 to SEQ ID NO: 232 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 229 to SEQ ID NO: 23282. The composition of any one of claims 78 to 81, wherein the BAFF-targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR3 comprising any one of SEQ ID NO: 233 to SEQ ID NO: 236 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 233 to SEQ ID NO: 23683. The composition of any one of claims 78 to 82, wherein the BAFF-targeting moiety comprises a heavy chain, wherein the heavy chain comprises a sequence that is at least 80%Attorney Docket No. 199830-740601 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: 208 to SEQ ID NO: 212.

84. The composition of any one of claims 78 to 82, wherein the BAFF -targeting moiety comprises a heavy chain variable region, wherein the heavy chain variable region 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 SEQ ID NO: 213 to SEQ ID NO: 216.

85. The composition of any one of claims 78 to 84, wherein the BAFF -targeting moiety comprises a light chain, wherein the light chain comprises a CDR1 comprising any one of SEQ ID NO: 237 to SEQ ID NO: 240 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 237 to SEQ ID NO: 24086. The composition of any one of claims 78 to 85, wherein the BAFF -targeting moiety comprises a light chain, wherein the light chain comprises a CDR2 comprising any one SEQ ID NO: 241 to SEQ ID NO: 244 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 241 to SEQ ID NO: 24487. The composition of any one of claims 78 to 86, wherein the BAFF -targeting moiety comprises a light chain, wherein the light chain comprises a CDR3 comprising any one of SEQ ID NO: 245 to SEQ ID NO: 248 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 245 to SEQ ID NO: 24888. The composition of any one of claims 78 to 87, wherein the BAFF -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 SEQ ID NO: 217 to SEQ ID NO: 220.

89. The composition of any one of claims 78 to 88, wherein the BAFF -targeting moiety comprises a light chain variable region, wherein the light chain variable region 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 SEQ ID NO: 221 to SEQ ID NO: 22490. The composition of any one of claims 78 to 89, wherein the BAFF -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 fragmentAttorney Docket No. 199830-740601 crystallizable (Fc) domain, a single chain variable fragment, a minibody, a nanobody (VHH), and any combination thereof.

91. The composition of any one of any one of claims 78 to 90, 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.

92. The composition of any one of claims 78 to 91, 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 to SEQ ID NO: 61.

93. The composition of any one of claims 78 to 92, wherein the CD-40 targeting moiety comprises a light chain, 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: 137.

94. The composition of any one of claims 78-93, 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.

95. The composition of claim 94, wherein the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 heavy chain constant region.

96. The composition of any one of claims 78-94, 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.Attorney Docket No. 199830-74060197. The composition of any one of claims 78-96, wherein the composition does not bind to CD-40 ligand (CD40L).

98. The composition of any one of claims 78-97, wherein the composition further comprises a half-life extension moiety.

99. The composition of claim 98, wherein the half-life extension moiety is an albumin.

100. The composition of any one of claims 78-99, wherein the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an N-linked glycan.

101. The composition of any one of claims 78-100, wherein the CD-40 targeting moiety comprises two light chains.

102. The composition of any one of claims 78-101, wherein the CD-40 targeting moiety comprises two heavy chains.

103. The composition of any one of claims 78-102, wherein the CD-40 targeting moiety comprises one heavy chain and one light chain.

104. The composition of any one of claims 78-103, wherein the CD-40 targeting moiety comprises two light chains and two heavy chains.

105. The composition of any one of claims 78-104, wherein the CD-40 targeting moiety or the BAFF targeting moiety comprises an IgA fragment.

106. The composition of any one of claims 78-105, wherein the CD-40 targeting moiety or the BAFF targeting moiety comprises a constant domain comprising one or more amino acid substitutions that increase multimerization of the CD-40 targeting moiety and the BAFF targeting moiety.

107. The composition of claim 106, 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 having a larger side chain volume than the original amino acid residue.

108. The composition of 107, wherein the import amino acid residue comprises a phenylalanine (F), a tyrosine (Y), or a tryptophan (W).

109. The composition of claim 107, 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.

110. The composition of claim 107, 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 comprises a cysteine (C) relative to the original amino acid residue.

111. A composition comprising:Attorney Docket No. 199830-740601(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: 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 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 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; and(b) an APRIL-targeting moiety.

112. The composition of claim 111, wherein the APRIL-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.

113. The composition of claim 111 or claim 112, wherein the APRIL-targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR1 comprising SEQ ID NO: 230 or SEQ ID NO: 231 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to SEQ ID NO: 261 or SEQ ID NO: 262.

114. The composition of any one of claims 111 to 113, wherein the APRIL-targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR2 comprising any one of SEQ ID NO: 232 to SEQ ID NO: 233 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 263 to SEQ ID NO: 264115. The composition of any one of claims 111 to 114, wherein the APRIL-targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR3 comprising any one of SEQ ID NO: 234 to SEQ ID hlO: 235 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 265 to SEQ ID NO: 266116. The composition of any one of claims 111 to 115, wherein the APRIL-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,Attorney Docket No. 199830-740601 at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 253 or SEQ ID NO: 254117. The composition of any one of claims 111 to 116, wherein the APRIL-targeting moiety comprises a heavy chain variable region, wherein the heavy chain variable region 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 SEQ ID NO: 255 or SEQ ID NO: 256118. The composition of any one of claims 111 to 117, wherein the APRIL-targeting moiety comprises a light chain, wherein the light chain comprises a CDR1 comprising SEQ ID NO: 267 or SEQ ID NO: 268 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to SEQ ID NO: 267 or SEQ ID NO: 268.

119. The composition of any one of claims 111 to 118, wherein the APRIL-targeting moiety comprises a light chain, wherein the light chain comprises a CDR2 comprising SEQ ID NO: 269 or SEQ ID NO: 270 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to SEQ ID NO: 269 or SEQ ID NO: 270.

120. The composition of any one of claims 111 to 119, wherein the APRIL-targeting moiety comprises a light chain, wherein the light chain comprises a CDR3 comprising SEQ ID NO: 271 or SEQ ID NO: 272 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 271 or SEQ ID NO: 272.

121. The composition of any one of claims 111 to 120, wherein the APRIL-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 SEQ ID NO: 257 or SEQ ID NO: 258122. The composition of any one of claims 111 to 121, wherein the APRIL-targeting moiety comprises a light chain variable region, wherein the light chain variable region 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 SEQ ID NO: 259 or SEQ ID NO: 260123. The composition of any one of claims 111 to 122, wherein the APRIL-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.Attorney Docket No. 199830-740601124. The composition of any one of claims 111 to 123, 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.

125. The composition of any one of claims 111 to 124, 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 to SEQ ID NO: 61.

126. The composition of any one of claims 111 to 125, wherein the CD-40 targeting moiety comprises a light chain, 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: 137.

127. The composition of any one of claims 111 to 126, 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.

128. The composition of claim 127, wherein the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 heavy chain constant region.

129. The composition of any one of claims 111 to 128, 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.

130. The composition of any one of claims 111 to 129, wherein the composition does not bind to CD-40 ligand (CD40L).

131. The composition of any one of claims 111 to 130, wherein the composition further comprises a half-life extension moiety.Attorney Docket No. 199830-740601132. The composition of claim 131, wherein the half-life extension moiety is an albumin.

133. The composition of any one of claims 111 to 132, wherein the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an N-linked glycan.

134. The composition of any one of claims 111 to 133, wherein the CD-40 targeting moiety comprises two light chains.

135. The composition of any one of claims 111 to 134, wherein the CD-40 targeting moiety comprises two heavy chains.

136. The composition of any one of claims 111 to 135, wherein the CD-40 targeting moiety comprises one heavy chain and one light chain.

137. The composition of any one of claims 111 to 136, wherein the CD-40 targeting moiety comprises two light chains and two heavy chains.

138. The composition of any one of claims 111 to 137, wherein the CD-40 targeting moiety or the APRIL-targeting moiety comprises an IgA fragment.

139. The composition of any one of claims 111 to 138, wherein the CD-40 targeting moiety or the APRIL targeting moiety comprises a constant domain comprising one or more amino acid substitutions that increase multimerization of the CD-40 targeting moiety and the APRIL- targeting moiety.

140. The composition of claim 139, 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 having a larger side chain volume than the original amino acid residue.

141. The composition of claim 140, wherein the import amino acid residue comprises a phenylalanine (F), a tyrosine (Y), or a tryptophan (W).

142. The composition of claim 139, 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, aY to V amino acid substation, or any combination thereof143. The composition of claim 139, 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 comprises a cysteine (C) relative to the original amino acid residue.

144. A composition comprising:(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: 19 or a functional variant thereof, wherein the functional variant comprises one or twoAttorney Docket No. 199830-740601 amino acid substitutions 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 one or two amino acid substitutions as compared to SEQ ID NO: 20 to SEQ ID NO: 33; and(iii) a CDR3 comprising 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; and(b) an interferon receptor (IFNR)-targeting moiety.

145. The composition of claim 144, wherein the IFNR-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.

146. The composition of claim 144 or claim 145, 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.

147. The composition of any one of claims 144 to 146, 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 to SEQ ID NO: 61.

148. The composition of any one of claims 144-147, wherein the CD-40 targeting moiety comprises a light chain, 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: 137.Attorney Docket No. 199830-740601149. The composition of any one of claims 144 to 148, 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.

150. The composition of claim 149, wherein the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 heavy chain constant region.

151. The composition of any one of claims 144 to 150, 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.

152. The composition of any one of claims 144 to 151, wherein the composition does not bind to CD-40 ligand (CD40L).

153. The composition of any one of claims 144 to 152, wherein the composition further comprises a half-life extension moiety.

154. The composition of claim 153, wherein the half-life extension moiety is an albumin.

155. The composition of any one of claims 144 to 154, wherein the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an N-linked glycan.

156. The composition of any one of claims 144 to 155, wherein the CD-40 targeting moiety comprises two light chains.

157. The composition of any one of claims 142 to 156, wherein the CD-40 targeting moiety comprises two heavy chains.

158. The composition of any one of claims 144 to 157, wherein the CD-40 targeting moiety comprises one heavy chain and one light chain.

159. The composition of any one of claims 144 to 158, wherein the CD-40 targeting moiety comprises two light chains and two heavy chains.

160. The composition of any one of claims 144 to 159, wherein the CD-40 targeting moiety or the IFNR-targeting moiety comprises an IgA fragment.

161. The composition of any one of claims 144 to 160, wherein the CD-40 targeting moiety or the IFNR-targeting moiety comprises a constant domain comprising one or more amino acid substitutions that increase multimerization of the CD-40 targeting moiety and the IFNR targeting moiety.

162. The composition of claim 161, 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 having a larger side chain volume than the original amino acid residue.Attorney Docket No. 199830-740601163. The composition of claim 162, wherein the import amino acid residue comprises a phenylalanine (F), a tyrosine (Y), or a tryptophan (W).

164. The composition of claim 161, 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 thereof165. The composition of claim 161, 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 comprises a cysteine (C) relative to the original amino acid residue.

166. A polypeptide construct comprising:(a) a first CD-40 targeting moiety and a second CD-40 targeting moiety, wherein the CD-40 targeting moieties comprises a heavy chain comprising:(i) a CDR1 1 comprising 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 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 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;(b) an IFNR targeting moiety.

167. A polypeptide construct comprising:(a) a CD-40 targeting moiety, wherein the CD-40 targeting moieties comprises a heavy chain comprising:(i) a CDR1 1 comprising 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 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; andAttorney Docket No. 199830-740601(iii) a CDR3 comprising 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;(b) a CD-20 targeting moiety; and(c) a BAFF targeting moiety.

168. A polypeptide construct comprising:(a) a CD-40 targeting moiety, wherein the CD-40 targeting moieties comprises a heavy chain comprising:(i) a CDR1 1 comprising 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 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 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;(b) a CD-20 targeting moiety; and(c) an APRIL targeting moiety.

169. A polypeptide construct comprising:(a) a CD-40 targeting moiety, wherein the CD-40 targeting moieties comprises a heavy chain comprising:(i) a CDR1 1 comprising 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 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 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;(b) a CD-20 targeting moiety; and(c) an IFNR targeting moiety.Attorney Docket No. 199830-740601170. A polypeptide construct comprising: a CD-40 targeting moiety, wherein the CD-40 targeting moieties comprises a heavy chain comprising:(i) a CDR1 1 comprising 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 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 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;(b) a BAFF targeting moiety; and(c) an IFNR targeting moiety.

171. A polypeptide construct comprising:(a) a CD-40 targeting moiety, wherein the CD-40 targeting moieties comprises a heavy chain comprising:(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 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 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 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;(b) a BAFF targeting moiety; and(c) an APRIL targeting moiety.

172. A polypeptide construct comprising:(a) a CD-40 targeting moiety, wherein the CD-40 targeting moieties comprises a heavy chain comprising:(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 one or twoAttorney Docket No. 199830-740601 amino acid substitutions 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 one or two amino acid substitutions as compared to SEQ ID NO: 20 to SEQ ID NO: 33; and(iii) a CDR3 comprising 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;(b) an APRIL targeting moiety; and(c) an IFNR targeting moiety.

173. The polypeptide construct of any preceding claim, wherein the polypeptide construct 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), relative to (a)-(h) prior to contact with the polypeptide construct.

174. A nucleic acid encoding the bispecific polypeptide construct of any preceding claim, the composition of any preceding claim, or the engineered polypeptide of any preceding claim.

175. A vector comprising the nucleic acid of claim 174.

176. A cell comprising the nucleic acid of claim 174 or the vector of claim 175.

177. A pharmaceutical composition comprising the bispecific polypeptide construct of any preceding claim, the composition of any preceding claim, or the engineered polypeptide of any preceding claim; and a pharmaceutically acceptable carrier, excipient, or diluent.

178. A drug delivery device, wherein the drug delivery device comprises a reservoir comprising the pharmaceutical composition of claim 177.

179. A method of treating a disease in a human subject, the method comprising:Attorney Docket No. 199830-740601 administering to the human subject a therapeutically effective amount of the pharmaceutical composition of claim 177, thereby treating the disease in the human subject.

180. The method of claim 179, wherein the administering comprises local administration or systemic administration.

181. The method of claim 179 or claim 180, wherein 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.

182. The method of any one of claims 178 to 181, wherein 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.

183. The method of any one of claims 178 to 181, wherein the disease comprises Crohn’sDisease or inflammatory bowel disease.

184. The method of any one of claims 178 to 181, wherein the disease comprises systemic lupus erythematosus.

185. The method of any one of claims 178 to 181, wherein the disease comprises scleroderma.

186. The method of any one of claims 178 to 181, wherein the disease comprises vasculitis.

187. The method of any one of claims 178 to 181, wherein the disease comprises pemphigus vulgaris.

188. The method of any one of claims 178 to 181, wherein the disease comprises multiple sclerosis.

189. The method of any one of claims 178 to 181, wherein the disease comprises rheumatoid arthritis.

190. The method of any one of claims 178 to 181, wherein the disease comprises amyloidosis.

191. The method of any one of claims 178 to 181, wherein the disease comprises Sjogren’s Disease.

192. The method of any one of claims 178 to 181, wherein the disease comprises lupus nephritis.

193. A method of inducing immune tolerance in a subject, the method comprising:Attorney Docket No. 199830-740601 administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 177, thereby inducing immune tolerance in the subject.

194. The method of claim 193, wherein the subject has or is to receive a transplantation or a gene therapy.

195. The method of claim 193, wherein the method further comprises administering an immunosuppressive agent to the subject.

196. The method of claim 193, wherein the subject has or is suspected of having graft versus host disease.

197. The method of claim 193, wherein the administering comprises local administration or systemic administration.

198. The method of claim 193, wherein 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.

199. A method of reducing inflammation in a subject, the method comprising: administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim, thereby reducing inflammation in the subject relative to a level of inflammation in the subject prior to administering the pharmaceutical composition.

200. The method of claim 198, wherein the administering comprises local administration or systemic administration.

201. The method of claim 198 or claim 199, wherein 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.

202. The method of any one of claims 198 to 200, wherein the subject has or is suspected of having an autoimmune disease.

203. The method of any one of claims 198 to 200, wherein the subject has or is suspected of having an allergic reaction to an antigen.

204. The method of any one of claims 198 to 200, wherein the subject has or is suspected of having increased IgE antibodies relative to a healthy subject.

205. The method of any one of claims 198 to 203, wherein the method further comprises administering an immunosuppressive agent to the subject.Attorney Docket No. 199830-740601206. The method of claim 201, wherein the autoimmune disease comprises Crohn’s Disease or inflammatory bowel disease.

207. The method of claim 201, wherein the autoimmune disease comprises systemic lupus erythematosus.

208. The method of claim 201, wherein the autoimmune disease comprises scleroderma.

209. The method of claim 201, wherein the autoimmune disease comprises vasculitis.

210. The method of claim 201, wherein the autoimmune disease comprises pemphigus vulgaris.

211. The method of claim 201, wherein the autoimmune disease comprises multiple sclerosis.

212. The method of claim 201, wherein the autoimmune disease comprises rheumatoid arthritis.

213. The method of claim 201, wherein the autoimmune disease comprises Sjogren’s Disease.

214. The method of claim 201, wherein the autoimmune disease comprises lupus nephritis.

215. The method of any one of claims 198 to 213, wherein the subject has or is suspected of having amyloidosis.

216. The method of any one of claims 178 to 214, wherein the administering reduces the number of CD19+CD20+B cells in the subject relative to the number of CD19+CD20+B cells in the subject prior to the administering.

217. The method of any one of claims 178 to 215, wherein the administering reduces the number of memory B cells in the subject relative to the number of memory B cells in the subject prior to the administering.

218. A method of treating cancer in a subject, the method comprising: administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 177, thereby treating the cancer in the subject.

219. The method of claim 218, wherein the cancer is a lymphoma or a leukemia.

220. The method of claim 219, wherein the lymphoma is a follicular lymphoma, a marginal zone lymphoma, or a mantle cell lymphoma.

221. The method of claim 218, wherein the leukemia is an acute lymphoblastic leukemia.

222. A composition for use in treating systemic lupus erythematosus, wherein the composition comprises: a bispecific polypeptide construct comprising:Attorney Docket No. 199830-740601(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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and(b) a CD-20 targeting moiety, wherein the composition is administered to a subject in need thereof thereby treating systemic lupus erythematosus in the subject.

223. A composition for use in treating multiple sclerosis, wherein the composition comprises: a bispecific polypeptide construct comprising:(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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and(b) a CD-20 targeting moiety,Attorney Docket No. 199830-740601 wherein the composition is administered to a subject in need thereof, thereby treating multiple sclerosis in the subject.

224. A composition for use in treating an autoimmune disease, wherein the composition comprises: a bispecific polypeptide construct comprising:(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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and(b) a CD-20 targeting moiety, wherein the composition is administered to a subject in need thereof, thereby treating the autoimmune disease in the subject.

225. A composition for use in treating cancer in a subject, wherein the composition comprises: a bispecific polypeptide construct comprising:(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 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 any one of SEQ ID NO: 20 to SEQ ID NO: 33; andAttorney Docket No. 199830-740601(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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and(b) a CD-20 targeting moiety, wherein the composition is administered to a subject in need thereof thereby treating cancer in the subject.

226. A composition for use in treating cancer in a subject, wherein the composition comprises: a tetravalent polypeptide construct comprising:(a) two CD-40 targeting moieties; and(b) two CD-20 targeting moieties, wherein the composition is administered to a subject in need thereof thereby treating cancer in the subject.

227. An injectable formulation comprising any one of the compositions of any preceding claim.

228. An injectable formulation comprising: a polypeptide construct comprising:(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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44229. An injectable formulation comprising: a polypeptide construct comprising:Attorney Docket No. 199830-740601(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 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 any one of 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 any one of SEQ ID NO: 34 to SEQ ID NO: 44; and(b) a CD-20 targeting moiety.

230. An injectable formulation comprising: 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.

231. An injectable formulation comprising: a polypeptide construct comprising:(a) 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 twoAttorney Docket No. 199830-740601 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; and(b) a CD-20 targeting moiety.

232. The injectable formulation of any preceding claim, 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 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: 169233. The injectable formulation of any preceding claim, 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: 174234. The injectable formulation of any preceding claim, 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: 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: 178235. The injectable formulation of any preceding claim, 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 SEQ ID NO: 179 to SEQ ID NO: 185236. The injectable formulation of any preceding claim, wherein the CD-20 targeting moiety comprises a light chain, wherein the light chain comprises a CDR1 comprising any one of SEQ ID NO: 105 to SEQ ID NO: 107 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 105 to SEQ ID NO: 107Attorney Docket No. 199830-740601237. The injectable formulation of any preceding claim, wherein the CD-20 targeting moiety comprises a light chain, wherein the light chain comprises a CDR2 comprising any one SEQ ID NO: 108 to SEQ ID NO: 111 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 108 to SEQ ID NO: 111238. The injectable formulation of any preceding claim, wherein the CD-20 targeting moiety comprises a light chain, wherein the light chain comprises a CDR3 comprising any one of SEQ ID NO: 112 to SEQ ID NO: 115 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 112 to SEQ ID NO: 115239. The injectable formulation of any preceding claim, wherein the polypeptide construct comprises a sequence that is at least 80% identical to SEQ ID NO: 39.

240. The injectable formulation of any preceding claim, wherein the polypeptide construct comprises a sequence that is at least 80% identical to SEQ ID NO: 75.

241. The injectable formulation of any preceding claim, wherein the polypeptide construct comprises a sequence that is at least 80% identical to any one of SEQ ID NO: 139 to 178242. The composition of any preceding claim, wherein the composition comprises a polypeptide construct comprising a sequence that is at least 80% identical to any one of SEQ ID NO: 139 to 178243. The bispecific polypeptide construct of any preceding claim, wherein the bispecific polypeptide construct comprises a sequence that is at least 80% identical to any one of SEQ ID NO: 139 to 178244. A composition comprising: 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: 1 to SEQ ID NO: 161; and / or 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: 164 to SEQ ID NO: 200.

245. A composition comprising: 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