April binding proteins, compositions, and methods of use thereof

Abstract

APRIL-binding proteins, related compositions, and related methods of use.

Description

APRIL BINDING PROTEINS, COMPOSITIONS, AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 709,969 (filed October 21, 2024), U.S. Provisional Application No. 63 / 744,331 (filed January 12, 2025), U.S. Provisional Application No. 63 / 750,247 (filed January 27, 2025), U.S. Provisional Application No. 63 / 808,404 (filed May 19, 2025) and U.S. Provisional Application No. 63 / 820,461 (filed June 9, 2025). The entire contents of the aforementioned applications are incorporated herein by reference.TECHNICAL FIELD

[0002] The present invention relates to APRIL binding proteins, and related nucleic acids, expression vectors, host cells, pharmaceutical compositions, methods of making, and methods of use.SEQUENCE LISTING

[0003] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 17, 2025 is named JDJ-074PC_SL.xml and is 631,668 bytes in size.BACKGROUND

[0004] The B cell-activating factor / a proliferation-inducing ligand (BAFT / APRIL) system promotes B cell survival and differentiation and is thought to play a prominent role in the pathogenesis of autoimmune diseases. APRIL inhibitors, such as APRIL monoclonal antibodies, are being investigated for treatment of autoimmune disorders such as systemic lupus erythematosus and IgA nephropathy. However, therapeutics based on blockade of APRIL have shown considerable variability in their affinity, potency, half-life and / or target- mediated drug disposition (TMDD). For example, formation of high molecular weight complexes by anti-APRIL antibodies can greatly affect antibody potency. Moreover, rapid clearance of anti-APRIL antibodies in vivo by TMDD can have a significant detrimental effect on antibody potency.

[0005] There remains a need for improved therapeutics targeting APRIL.SUMMARY

[0006] The present invention addresses this need with APRIL-binding proteins that exhibit desirable properties for therapeutic use, as well as related compositions and methods. The APRIL-binding proteins of the disclosure were identified based on their having improved properties, e.g., relative to existing APRIL-targeted therapeutics, which can lead to enhanced therapeutic efficacy of the APRIL-binding proteins. For example, in embodiments, APRIL- binding proteins of the disclosure were selected for ultra-high binding affinity (e.g., femtomolar affinity) to APRIL. In embodiments, APRIL-binding proteins of the disclosure were selected for their ability to avoid high molecular weight complex formation while maintaining high affinity binding to APRIL. In embodiments, APRIL-binding proteins of the disclosure were selected based on their exhibiting reduced target-mediated drug disposition (TMDD). In embodiments, APRIL-binding proteins of the disclosure were selected based on their exhibiting a long plasma half-life (T1 / 2) (e.g., greater than 25 days in non-human primates). In embodiments, APRIL-binding proteins of the disclosure were selected based on their exhibiting reduced effector function(s) (e.g., Fc-mediated effector function(s)). Moreover, the APRIL-binding proteins of the disclosure have been demonstrated to inhibit the interaction of APRIL with TACI and BCMA (i.e., they exhibit functional blocking activity) and to reduce IgA production and inhibit plasma cell proliferation in vivo.

[0007] Accordingly, in some embodiments, an APRIL-binding protein of the disclosure exhibits one or more of the following features (e.g., relative to existing APRIL-targeted therapeutics): (i) ultra-high affinity binding (e.g., femtomolar affinity) to APRIL; (ii) reduced (e.g., minimal) high molecular weight complex formation; (iii) reduced (e.g., minimal) TMDD in vivo; (iv) a long plasma T1 / 2; and / or (v) reduced effector function(s) (e.g., Fc-mediated effector function(s)). In embodiments, an APRIL-binding protein of the disclosure exhibits two, three, four or all five of the afore-mentioned features. In embodiments, the APRIL- binding protein inhibits the interaction of APRIL with TACI and / or BCMA. In embodiments, the APRIL-binding protein reduces IgA production in vivo. In embodiments, the APRIL- binding protein inhibits plasma cell proliferation in vivo.

[0008] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity-determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; and CDR-H3 comprising the amino acid sequence of SEQ ID NO:5; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 10; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 11 ; or (c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 14; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 15; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 16.

[0009] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 1.

[0010] In some embodiments, provided APRIL-binding proteins further comprise a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 12; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 13; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 17; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 2.

[0011] In some embodiments, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR- H1 comprising the amino acid sequence of SEQ ID NO: 3; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; CDR- L2 comprising the amino acid sequence of SEQ ID NO: 7; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 10; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 11 ; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 12; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 13; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions:CDR-H1 comprising the amino acid sequence of SEQ ID NO: 14; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 15; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 16; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 17; CDR- L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 18.

[0012] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 21 ; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 22; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 27; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 28; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 29; or (c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 33; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 34.

[0013] In some embodiments, the VII comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 19.

[0014] In some embodiments, the APRIL-binding protein further comprises a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 24; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 26; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 30; CDR-L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 31; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 35; CDR-L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 36. In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 20.

[0015] In some embodiments, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR- H1 comprising the amino acid sequence of SEQ ID NO: 21; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 22; and CDR-H3 comprising the amino acid sequence of SEQID NO: 23; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 24; CDR- L2 comprising the amino acid sequence of SEQ ID NO: 25; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 26; (b) (i) a heavy chain variable domain (VII) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 27; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 28; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 29; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 30; CDR-L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 31; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 33; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 34; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 35; CDR- L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 36.

[0016] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 39; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 40; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 41; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 45; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 46; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 47; or (c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 50; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 51; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 52.

[0017] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 37.

[0018] In some embodiments, provided APRIL-binding proteins further comprise a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 42; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 43; and CDR-L3 comprising the amino acid sequence of SEQ IDNO: 44; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 48; CDR-L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 49; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 53; CDR-L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 54.

[0019] In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 38.

[0020] In some embodiments, provided are APRIL-binding proteins comprising: (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR- H1 comprising the amino acid sequence of SEQ ID NO: 39; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 40; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 41; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 42; CDR- L2 comprising the amino acid sequence of SEQ ID NO: 43; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 44; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 45; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 46; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 47; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 48; CDR-L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 49; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions CDR-HI comprising the amino acid sequence of SEQ ID NO: 50; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 51; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 52; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 53; CDR- L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 54.

[0021] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-HI comprising the amino acid sequence of SEQ ID NO: 57; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 58; and CDR-H3 comprising the amino acid sequence of SEQ IDNO: 59; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 63; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 64; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 65; or (c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 69; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 70.

[0022] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 55.

[0023] In some embodiments, provided APRIL-binding proteins further comprise a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 60; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 61 ; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 62; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 66; CDR-L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 67; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 71; CDR-L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 72. In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 56.

[0024] In some embodiments, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR- H1 comprising the amino acid sequence of SEQ ID NO: 57; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 58; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 59; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 60; CDR- L2 comprising the amino acid sequence of SEQ ID NO: 61; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 62; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 63; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 64; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 65; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 66; CDR-L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 67; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions:CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 69; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 70; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 71; CDR- L2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 72.

[0025] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 75; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 76; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 77; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 81; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 82; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 83; or (c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 87; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 73.

[0026] In some embodiments, provided APRIL-binding proteins further comprise a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 78; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 79; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 80; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 84; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 85; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 89; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 92.

[0027] In some embodiments, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR- HI comprising the amino acid sequence of SEQ ID NO: 75; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 76; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 77; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 78; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 79; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 80; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 81; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 82; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 83; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 84; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 85; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 87; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 88; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 89; CDR- L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 90.

[0028] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 93; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 94; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 95; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 99; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 100; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 101 ; or (c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 104; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 105; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 106. In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 91.

[0029] In some embodiments, provided APRIL-binding proteins further comprise a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 96; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 97; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 98; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 102; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequenceof SEQ ID NO: 103; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 107; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 108. In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 92.

[0030] In some embodiments, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR- H1 comprising the amino acid sequence of SEQ ID NO: 93; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 94; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 95; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 96; CDR- L2 comprising the amino acid sequence of SEQ ID NO: 97; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 98; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 99; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 100; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 101; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 102; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 103; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 104; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 105; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 106; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 107; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 108.

[0031] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 11 1; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 112; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 113; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 117; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 118; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 119; or (c) CDR-H1 comprising the amino acidsequence of SEQ ID NO: 122; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 123; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 124. In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 109.

[0032] In some embodiments, APRIL-binding proteins further comprise a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 114; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 115; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 116; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 120; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 121; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 125; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 126. In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 110.

[0033] In one aspect, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VII) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 111; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 112; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 113; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 114; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 115; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 116; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 117; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 118; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 119; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 120; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 121; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 122; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 123; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 124; and (ii) a light chain variable domain (VL) comprisingcomplementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 125; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 126.

[0034] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 129; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 130; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 131; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 135; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 136; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 137; or (c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 140; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 141; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 142. In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 127.

[0035] In some embodiments, APRIL-binding proteins further comprise a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 132; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 133; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 134; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 138; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 139; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 143; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 144. In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 128.

[0036] In some embodiments, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR- H1 comprising the amino acid sequence of SEQ ID NO: 129; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 130; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 131; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 132; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 133; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 134; (b) (i) a heavy chain variable domain (VH)comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 135: CDR-H2 comprising the amino acid sequence of SEQ ID NO: 136; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 137; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 138; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 139; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 140; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 141; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 142; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 143; CDR-L2 comprising the amino acid sequence DAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 144.

[0037] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) that is at least 95% identical to that of SEQ ID NO: 263, wherein the VH comprises a heavy chain complementarity-determining region, CDR-H3, comprising the amino acid sequence of SEQ ID NO: 267, 272, or 276.

[0038] In some embodiments, (i) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 267 and the VH further comprises complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 266; (ii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 272 and the VH further comprises complementarity-determining regions: CDR- H1 comprising the amino acid sequence of SEQ ID NO: 270; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 271; or (iii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 276 and the VH further comprises complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 274; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 275.

[0039] In some embodiments, the APRIL-binding protein further comprises a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 268; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 269; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 273; CDR-L2comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 269; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 277; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 278.

[0040] In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 264.

[0041] In one aspect, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 266; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 267; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 268; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 269; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 270; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 271; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 272; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 273; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 269; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 274; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 275; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 276; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 277; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 278.

[0042] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) that is at least 95% identical to that of SEQ ID NO: 279, wherein the VH comprises a heavy chain complementarity-determining region, CDR-H3, comprising the amino acid sequence of SEQ ID NO: 267, 272, or 276.

[0043] In some embodiments, (i) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 267 and the VH further comprises complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 281 ; (ii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 272 and the VH further comprises complementarity-determining regions: CDR- H1 comprising the amino acid sequence of SEQ ID NO: 284; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 285; or (iii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 276 and the VH further comprises complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 287; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 288.

[0044] In some embodiments, the APRIL -binding protein further comprises a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 282; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 283; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 286; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 283; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 289; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 290.

[0045] In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 280.

[0046] In one aspect, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 281 ; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 267; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 282; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 283; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 284; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 285; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 272; and (ii) a lightchain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 286: CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 283; or (c) (i) a heavy chain variable domain (VII) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 287; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 288; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 276; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 289; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 290.

[0047] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) that is at least 95% identical to that of SEQ ID NO: 291, wherein the VH comprises a heavy chain complementarity-determining region, CDR-H3, comprising the amino acid sequence of SEQ ID NO: 294, 297, or 300.

[0048] In some embodiments, (i) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 294 and the VII further comprises complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 293; (ii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 297 and the VH further comprises complementarity-determining regions: CDR- H1 comprising the amino acid sequence of SEQ ID NO: 284; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 296; or (iii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 300 and the VH further comprises complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 287; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 299.

[0049] In some embodiments, the APRIE-binding protein further comprises a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 268; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7: and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 295; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 273; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 295; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO:277; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 301.

[0050] In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 292.

[0051] In one aspect, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 293; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 294; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 268; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 295; (b) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 284; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 296; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 297; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 273; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 295; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 287; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 299; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 300; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-LI comprising the amino acid sequence of SEQ ID NO: 277; CDR-L2 comprising the amino acid sequence AAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 301.

[0052] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 305; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 306; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 311; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 312; or (c) CDR-H1 comprising the amino acidsequence of SEQ ID NO: 32; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 314; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 315.

[0053] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 302. In some embodiments, the APRIL-binding protein further comprises a light chain variable domain (VL) comprising complementaritydetermining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 307; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 309; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 313; CDR-L2 comprising the amino acid sequence LGS; and CDR- L3 comprising the amino acid sequence of SEQ ID NO: 309; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 316; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 317.

[0054] In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 303.

[0055] In one aspect, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 305; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 306; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 307; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 309; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 311; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 312; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 313; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 309; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 314; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 315; and (ii) a light chain variable domain (VL) comprisingcomplementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 316; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 317.

[0056] In one aspect, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 323; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 324; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 328; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 324; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 332; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.

[0057] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 318. In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 319.

[0058] In one aspect, provided are APRIL-binding proteins comprising: (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321 ; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 323; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; (b) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 328; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or (c) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331 ; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 332; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.

[0059] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 334. In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 335.

[0060] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 339; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 341; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; or (c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 343; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331.

[0061] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 337.

[0062] In some embodiments, the APRIL-binding protein further comprises a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 340; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 342; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 344; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.

[0063] In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 338.

[0064] In one aspect, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 339; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 340; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 341; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 342; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 343; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 344; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.

[0065] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 347; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 350; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 351; or (c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 354; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331.

[0066] In some embodiments, the VII comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 345.

[0067] In some embodiments, the APRIL-binding protein further comprises a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 348; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 352; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 355; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 356.

[0068] In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 346.

[0069] In one aspect, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 347; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 348; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acidsequence of SEQ ID NO: 310; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 350; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 351; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 352; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 354; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 355; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 356.

[0070] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 359; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 361; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 351; or (c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 363; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331.

[0071] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 357.

[0072] In some embodiments, the APRIL-binding protein further comprises a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 360; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 362; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 364; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 356.

[0073] In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 358.

[0074] In one aspect, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 359; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 360; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 361; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 351; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 362; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 363; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 364; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 356.

[0075] In one aspect, provided are APRIL-binding proteins comprising: (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 367; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 368; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acidsequence of SEQ ID NO: 325; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 369; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 368; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 370; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 317.

[0076] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 365. In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 366.

[0077] In one aspect, provided are APRIL-binding proteins comprising: (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321 ; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 373; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 309; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 373; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 309; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; and CDR-H3 comprising the aminoacid sequence of SEQ ID NO: 331; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 374; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 317.

[0078] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 371.

[0079] In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 372.

[0080] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity -determining regions: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 347; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 377; (b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 379; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 350; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 380; or (c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 382; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 354; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 383.

[0081] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 375.

[0082] In some embodiments, the APRIL-binding protein further comprises a light chain variable domain (VL) comprising complementarity-determining regions: (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 378; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; (b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 381; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or (c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 384; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.

[0083] In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 376.

[0084] In one aspect, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 347; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 377; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 378; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 379; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 350; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 380; and (ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 381; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or (c) (i) a heavy chain variable domain (VH) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 382; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 354; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 383; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 384; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.

[0085] In one aspect, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 387; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 388; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 389; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 390; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 391; (b) (i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 392; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 393; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 394; and (ii) a lightchain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 395: CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 391; or (c) (i) a heavy chain variable domain (VII) comprising complementarity -determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 396; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 397; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 398; and (ii) a light chain variable domain (VL) comprising complementarity -determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 399; CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 400.

[0086] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 385. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 386.

[0087] In some embodiments, APRIL-binding proteins further comprise an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

[0088] In some embodiments, the APRIL-binding protein is an antibody or antigenbinding fragment thereof, e.g., a human antibody or antigen-binding fragment thereof.

[0089] In some embodiments, the antigen-binding fragment is a Fab, a F(ab’)2, a Fab’, a single-chain Fv (scFv), an Fv fragment, a Fd fragment, or a diabody.

[0090] In some embodiments, the antibody or antigen-binding fragment thereof comprises an Fc region, e.g., an IgGl , IgG2, or IgG4 Fc region. In some embodiments, the Fc region is an IgGl Fc region.

[0091] In some embodiments, the Fc region is a modified Fc region, e.g., a modified Fc region which comprises a half-life extending mutation or set of half-life extending mutations. In some embodiments, the set of half-life extending mutations is selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q31 1H / N434S (DHS).

[0092] In some embodiments, the modified Fc region comprises the specific combination of amino acid substitutions of LALA / YTE.

[0093] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 401, and the light chain comprises the amino acid sequence of SEQ ID NO: 402.

[0094] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 403, and the light chain comprises the amino acid sequence of SEQ ID NO: 404.

[0095] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 405, and the light chain comprises the amino acid sequence of SEQ ID NO: 406.

[0096] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 407, and the light chain comprises the amino acid sequence of SEQ ID NO: 408.

[0097] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 409, and the light chain comprises the amino acid sequence of SEQ ID NO: 410.

[0098] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:411, and the light chain comprises the amino acid sequence of SEQ ID NO: 410.

[0099] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:412, and the light chain comprises the amino acid sequence of SEQ ID NO: 413.

[0100] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 414, and the light chain comprises the amino acid sequence of SEQ ID NO: 415.

[0101] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 416, and the light chain comprises the amino acid sequence of SEQ ID NO: 417.

[0102] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 418, and the light chain comprises the amino acid sequence of SEQ ID NO: 419.

[0103] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 420, and the light chain comprises the amino acid sequence of SEQ ID NO: 421.

[0104] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 422, and the light chain comprises the amino acid sequence of SEQ ID NO: 423.

[0105] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 424, and the light chain comprises the amino acid sequence of SEQ ID NO: 425.

[0106] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 426, and the light chain comprises the amino acid sequence of SEQ ID NO: 427.

[0107] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 428, and the light chain comprises the amino acid sequence of SEQ ID NO: 429.

[0108] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 430, and the light chain comprises the amino acid sequence of SEQ ID NO: 431.

[0109] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 432, and the light chain comprises the amino acid sequence of SEQ ID NO: 433.

[0110] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 434, and the light chain comprises the amino acid sequence of SEQ ID NO: 435.

[0111] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 436, and the light chain comprises the amino acid sequence of SEQ ID NO: 437.

[0112] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 438, and the light chain comprises the amino acid sequence of SEQ ID NO: 439.

[0113] In one aspect, provided are APRIL-binding proteins comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 440, and the light chain comprises the amino acid sequence of SEQ ID NO: 441.

[0114] In one aspect, provided are isolated nucleic acids encoding an APRIL-binding protein as disclosed herein.

[0115] In one aspect, provided are expression vectors comprising isolated nucleic acids as disclosed herein.

[0116] In one aspect, provided are host cells comprising isolated nucleic acid molecules or expression vectors as disclosed herein. In another aspect, provided is a method of preparing an APRIL-binding protein of the disclosure by culturing the host cells comprising a nucleic acid molecule(s) or expression vector(s) encoding an APRIL-binding protein of the disclosure such that the APRIL-binding protein is expressed by the host cell. The method of preparing the APRIL-binding protein can further comprise isolating the APRIL-binding protein from the host cell or the culture supernatant thereof.

[0117] In one aspect, provided are pharmaceutical compositions comprising an APRIL- binding protein as disclosed herein and a pharmaceutically acceptable carrier.

[0118] In one aspect, provided are methods comprising a step of administering to a subject in need thereof an effective amount of an APRIL-binding protein or a pharmaceutical composition as disclosed herein. In some embodiments, the subject has an autoimmune or inflammatory disease, for example, a disorder selected from the group consisting of IgA nephropathy (IgAN), myasthenia gravis, systemic lupus erythematosus, membranous glomerulonephritis, Sjbgrens disease, lupus nephritis, immune thrombocytopenia, acquired (autoimmune) hemolytic anemia, cold agglutinin disease (CAD), autoimmune hepatitis, multiple sclerosis, pemphigus vulgaris, rheumatoid arthritis, hidradenitis suppurativa, ANCA- associated vasculitis (AAV), IgA Vasculitis, Minimal Change Disease (MCD), Focal Segmental Glomerulosclerosis (FSGS), Primary Nephrotic Syndrome, Systemic Sclerosis, Antineutrophil Cytoplasmic Antibody-associated Vasculitis, Nephritis, anti-NMDAR and anti-LGIl encephalitis, Connective tissue disease-associated thrombocytopenia, and Celiac Disease. In some embodiments, the autoimmune or inflammatory disease is IgAN.

[0119] In some embodiments, the subject has an allergic disease or disorder, such as food allergies, respiratory allergies, chemical allergies, asthma, hives, atopic dermatitis (eczema) or contact dermatitis.

[0120] In some embodiments, the subject has an IgM-mediated disease. In some embodiments, the IgM-mediated disease is selected from the group consisting of multifocal motor neuropathy (“MMN”), anti-MAG (myelin-associated glycoprotein) neuropathy, and cold agglutinin disease (“CAD”).

[0121] In some embodiments, the step of administering comprises systemic administration of the APRIL-binding protein, for example, systemic administration comprising intravenous or subcutaneous administration. In some embodiments, the APRIL-binding protein is administered in combination with one or more additional agents, such as one or more additional therapeutic agents used in the treatment of an autoimmune, inflammatory or allergic disease or disorder.BRIEF DESCRIPTION OF THE DRAWINGS

[0122] FIGs. 1A-1D show binding curves from surface plasmon resonance (SPR) experiments, for anti-APRIL antibodies against human APRIL (FIGs. 1A and 1C) or cynomolgus APRIL (FIGs. IB and ID).

[0123] FIGs. 2A-2D show results from enzyme-linked immunosorbent assay (ELISA) experiments to assess the ability of anti-APRIL antibodies to block binding of human APRIL to TACI (FIGs. 2A and 2C) or to BCMA (FIGs. 2B and 2D). The percentage of inhibition of TACI or BCMA binding to APRIL (y-axis) is plotted against the concentration of anti-APRIL antibody (x-axis). Results from experiments conducted using Reference Molecules 1, 2, 3, and / or 4 (which have the sequences as shown in Table 3) are shown for comparison.

[0124] FIGs. 3A- 3D show results from NFKB luciferase reporter experiments to assess the ability of anti-APRIL antibodies to block interaction between human APRIL and human TACI (FIGs. 3A and 3C) or human BCMA (FIGs. 3B and 3D). The percentage of inhibition of NFKB (y-axis) is plotted against the concentration of anti-APRIL antibody (x-axis). Results from experiments conducted using Reference Molecules 1, 2, 3, and / or 4 (which have the sequences as shown in Table 3) are shown for comparison.

[0125] FIGs. 4A and 4C show the concentration of anti-APRIL antibodies after administration in non-human primates. FIG. 4B and 4D show serum IgA production after administration of anti-APRIL antibodies after administration in non-human primates. Results from experiments conducted using Reference Molecule 1 (which has the sequences as shown in Table 3) are shown for comparison.

[0126] FIGs. 5A and 5B depict IgA production levels and plasma cell proliferation, respectively, as assessed in a translational assay of human plasma-cell function.

[0127] FIGs. 6A-6B show results from experiments administering Antibody A subcutaneously to non-human primates. FIG. 6A shows the concentration over time of subcutaneously (SC) administered Antibody A, at 10 mg / kg or 100 mg / kg, in non-human primates. FIG. 6B shows serum IgA production over time after SC administration of Antibody A at 10 mg / kg or 100 mg / kg in non-human primates.

[0128] FIGs. 7A-7D show results from additional experiments demonstrating that anti- APRIL Antibody A blocks binding of APRIL to BCM A and TACI and inhibits APRIL- mediated signaling. Competitive ELISA was used to assess the inhibition of binding of BCMA (FIG. 7A) or TACI (FIG. 7B) to APRIL in the presence of increasing amounts of Antibody A. NFKB luciferase reporter experiments were used to assess inhibition of receptor signaling by stimulating NFKB luciferase reporter cells expressing BCMA (FIG. 7C) or TACI (FIG. 7D) with recombinant APRIL in the presence of increasing amounts of Antibody A.

[0129] FIG. 8 shows a schematic diagram of the negative effects resulting from high molecular weight complex formation, including TMDD, rapid clearance of the antibody from the circulation, formation of anti -drug antibodies (ADA), unwanted complement activation and unwanted tissue accumulation.

[0130] FIG. 9 shows results from SEC-MALS experiments for APRIL alone.

[0131] FIG. 10 shows results from SEC-MALS experiments for Reference Molecule 1 in the absence (left panel) and presence (right panel) of APRIL.

[0132] FIG. 11 shows results from SEC-MALS experiments for Antibody A in the absence (left panel) and presence (right panel) of APRIL.

[0133] FIG. 12 shows a comparison of the SEC-MALS results for Reference Molecule 1 and Antibody A, with APRIL alone shown in the left panel, Reference Molecule 1 + APRIL shown in the middle panel and Antibody A + APRIL shown in the right panel.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0134] In various embodiments, provided are APRIL-binding proteins, compositions thereof, and methods of use thereof. In some embodiments, compared to existing monoclonal anti-APRIL antibodies in clinical development, provided APRIL-binding proteins exhibit increased binding affinity for APRIL, reduced high molecular weight complex formation, reduced TMDD, increased half-life extension and / or reduced Fc-mediated effector functions and have the potential to deliver improved dosing and convenience, a comparable safety profile and potentially increased clinical activity in certain autoimmune or inflammatory diseases such as IgA nephropathy (IgAN).Definitions

[0135] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0136] As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless the context clearly indicates otherwise. Thus, for example, reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. In another example, reference to a range of 1-5,000-fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth.

[0137] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0138] As used herein, the terms “about,” “approximately,” and “comparable to,” when used herein in reference to a value, refer to a value that is similar to the referenced value in the context of that referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about,” “approximately,” and “comparable to” in that context. For example, in some embodiments, the terms "about," “approximately,” and “comparable to” may encompass a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0139] 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 an Fc fragment of an antibody (e.g., an Fc fragment of a monoclonal antibody), or an antigenbinding 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 (V) and at least three constant regions (CHI, CH2 and CH3). The variable regions determine the binding specificity of the antibody. Each variable region contains three hypervariable regions known as complementarity determining regions (CDRs) flanked by four relatively conserved regions known as framework regions (FRs). The extent of the FRs and CDRs has been defined (Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917). The three CDRs in each variable region (e.g., light chain variable region or heavy chain variable region, with six CDRs total in a typical antibody format), referred to as CDR1, CDR2, and CDR3, collectively contribute to 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). An example of a chemically conjugated antibody is an antibody conjugated to a toxin moiety.

[0140] “Antibody-dependent cell-mediated cytotoxicity" or “ADCC” refers to a form of cytotoxicity in which secreted Ig bound onto Fc receptors (FcRs) present on certain cytotoxic cells (e.g., Natural Killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill thetarget cell with cytotoxins. The antibodies “arm” the cytotoxic cells and are absolutely required for such killing. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII and FcyRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in U.S. Pat. No. 5,500,362 or 5,821,337 may be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).

[0141] An “antigen-binding fragment” of an antibody, or “antibody fragment" comprises a portion of an intact antibody, which portion is still capable of antigen binding. In some embodiments, the antibody has a function in addition to that of antigen-binding, and an antigen-binding fragment retains that function. Typically, an antigen-binding fragment comprises the variable region of the antibody. Papain digestion of antibodies produce two identical antigen-binding fragments, called “Fab” fragments, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire light chain along with the variable region domain of the heavy chain (VH), and the first constant domain of one heavy chain (Cui). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and that is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CHI domain, including one or more cysteines from the antibody hinge region. Fab '-SH designates an Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments having hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0142] As used herein, the term “bivalent,” when used in reference to a binding protein, such as an antibody or an antibody -based binding protein, means that the binding protein is capable of binding two molecules of the antigen to which it specifically binds.

[0143] As used herein, the term “chimeric antibody” refers to an antibody that has a portion of its heavy and / or light chain identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass.

[0144] A “complementarity determining region” (abbreviated “CDR”) is a region of hypervariability interspersed within regions that are more conserved, termed “framework regions” (abbreviated “FR”). In some embodiments, the sequences of the framework regions are identical to the framework regions in human germline sequences. In some embodiments, the sequences of the framework regions are modified with respect to the human germline sequence.

[0145] As used herein, the phrase “complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (Clq) to antibodies (of the appropriate subclass) which are bound to their cognate antigen. To assess complement activation, a CDC assay, e.g., as described in Gazzano- Santoro et al., J. Immunol. Methods 202:163 (1996), may be performed.

[0146] As used herein, the terms “decrease,” “decreased,” “increase,” “increased,” or “reduction,” “reduced,” (e.g., in reference to therapeutic outcomes or effects) have meanings relative to a reference level, as further explained herein.

[0147] As used herein, antibody “effector functions” refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and which typically vary with the antibody isotype. Examples of antibody effector functions include, but are not limited to, Clq binding and complement dependent cytotoxicity, Fc receptor binding; antibody -dependent cell-mediated cytotoxicity (ADCC); phagocytosis, down regulation of cell surface receptors (e.g., B cell receptor), and B cell activation.

[0148] As used herein, the phrases “effective amount” and “therapeutically effective amount” of an agent (e.g., a binding protein or as described herein) are used interchangeably and refer to an amount effective, at dosages and for periods of time necessary, to achieve adesired therapeutic result. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. An effective amount may vary according to factors such as the type of disease (e.g., disease state, age, sex, and / or weight of the individual, and the ability of a binding protein (or pharmaceutical composition thereof) to elicit a desired response in the individual. An effective amount may also be an amount for which any toxic or detrimental effects of the binding protein or pharmaceutical composition thereof are outweighed by therapeutically beneficial effects.

[0149] As used herein, the term “epitope” is an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule (or binding protein), known as the paratope, and which is comprised of the six complementary- determining regions of the antibody (or binding protein). A single antigen may have more than one epitope. Epitopes may be conformational or linear. A conformational epitope is comprised of spatially juxtaposed amino acids from different segments of a linear polypeptide chain. A linear epitope is comprised of adjacent amino acid residues in a polypeptide chain.

[0150] The term “antibody that binds the same epitope” as another antibody is intended to encompass antibodies that interact with, i.e., bind to, the same structural region on human APRIL as a reference anti-APRIL antibody. The “same epitope” to which the antibodies bind may be a linear epitope or a conformational epitope formed by tertiary folding of the antigen.

[0151] The term “competing antibody” refers to an antibody that competes for binding to human APRIL with a reference anti-APRIL antibody, i.e., competitively inhibits binding of the reference anti-APRIL antibody to APRIL. A “competing antibody” may bind the same epitope on APRIL as the reference anti-APRIL antibody, may bind to an overlapping epitope or may sterically hinder the binding of the reference anti-APRIL antibody to APRIL.

[0152] Antibodies that recognize the same epitope or compete for binding can be identified using routine techniques. Such techniques include, for example, an immunoassay,which shows the ability of one antibody to block the binding of another antibody to a target antigen, i.e., a competitive binding assay. Competitive binding is determined in an assay in which the immunoglobulin under test inhibits specific binding of a reference antibody to a common antigen, such as APRIL. Numerous types of competitive binding assays are known, for example: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see Stahli et al., Methods in Enzymology 9:242 (1983)); solid phase direct biotin-avidin EIA (see Kirkland et al., J. Immunol. 137:3614 (1986)); solid phase direct labeled assay, solid phase direct labeled sandwich assay (see Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Press (1988)); solid phase direct label RIA using 1-125 label (see Morel et al., Mol. Immunol. 25(1):7 (1988)); solid phase direct biotin-avidin EIA (Cheung et al., Virology 176:546 (1990)); and direct labeled RIA. (Moldenhauer et a / ., Scand. J. Immunol. 32:77 (1990)). Typically, such an assay involves the use of purified antigen bound to a solid surface or cells bearing either of these, an unlabeled test immunoglobulin and a labeled reference immunoglobulin. Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test immunoglobulin. Usually, the test immunoglobulin is present in excess. Usually, when a competing antibody is present in excess, it will inhibit specific binding of a reference antibody to a common antigen by at least 50-55%, 55-60%, 60-65%, 65-70% 70-75% or more.

[0153] Other techniques include, for example, epitope mapping methods, such as, x-ray analyses of crystals of antigemantibody complexes which provides atomic resolution of the epitope. Other methods monitor the binding of the antibody to antigen fragments or mutated variations of the antigen where loss of binding due to a modification of an amino acid residue within the antigen sequence is often considered an indication of an epitope component. In addition, computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage display peptide libraries. The peptides are then regarded as leads for the definition of the epitope corresponding to the antibody used to screen the peptide library. For epitope mapping, computational algorithms have also been developed which have been shown to map conformational discontinuous epitopes.

[0154] An “Fc chain" of a dimeric Fc as used herein refers to one of the two polypeptides forming the dimeric Fc region, i.e. a polypeptide comprising C-terminal constant regions ofan immunoglobulin heavy chain, capable of stable association with another similar polypeptide. For example, an Fc chain of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence. An Fc chain or a dimeric Fc (“Fc region”) can be of any of a variety of Ig classes, e.g., IgA, IgD, IgE, IgG, or 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.

[0155] 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 sequence 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 (see, e.g., Janeway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)).Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (IT AM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (reviewed in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev.Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976); and Kim et al., J. Immunol. 24:249 (1994)).

[0156] As used herein, the term “humanized,” when used in reference to an antibody (or binding protein), refers to a form of a non-human (e.g., murine) antibody that is chimeric. A “humanized antibody” contains minimal sequences derived from non-human immunoglobulin. Typically, humanized antibodies are human immunoglobulins (recipient or acceptor antibody) in which hypervariable region residues of the recipient are replaced by hypervan able region residues from a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having a desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced bycorresponding non-human residues. Furthermore, humanized antibodies may comprise residues which are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance such as binding affinity. Generally, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin sequence although the framework regions may include one or more amino acid substitutions that improve binding affinity. In some embodiments, no more than six amino acid substitutions in the heavy chain and no more than three amino acid substitutions are used in the light chain in the framework region. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.

[0157] As used herein, the terms "high molecular weight complex", "high MW complex" and "BMW complex" are used interchangeably and are intended to refer to an aggregation of antibodies (e.g., anti-huAPRIL antibodies) or an aggregation of antibodies and their target antigen (e.g., anti-huAPRIL antibodies and huAPRIL) that forms a structure having a higher molecular weight than that of a typical antibody monomer. In some embodiments, an APRIL-binding protein of the disclosure (e.g., an anti-huAPRIL antibody) reduces or eliminates high MW complex formation, which can mitigate risks of immunogenicity and target-mediated drug disposition (TMDD). Formation of high MW complexes in an antibody preparation can be assessed by standard methods established in the art, non-limiting examples of which include size exclusion chromatography (SEC), SEC with multiple-angle light scattering (SEC-MALS), and mass spectrometry (MS). SEC separates proteins based on size, SEC-MALS allows purity and MW determination of molecules in native conditions and MS can directly measures the mass of intact antibody complexes. Additional approaches for assessing high MW complex formation have been described in the art, for example in Cramer et al. (2023) mAbs 15:2175312 and Strebl et al. (2024) Eur. J. Pharm. Sei. 203:106924.

[0158] As used herein, the term “large antigen-binding complex” refers to a high molecular weight complex comprising an antigen (e.g., APRIL) and protein which binds the antigen (e.g., APRIL-binding proteins) whose molecular weight is at least eight times that of the molecular weight of a monomer of the binding protein. In some embodiments, the molecular weight of the large antigen -binding complex is at least nine, at least ten, at least 11, at least 12, at least13, at least 14, at least 15, or at least 16 times that of the molecular weight of a monomer of the binding protein.

[0159] As used herein, the term “monovalent,” when used in reference to a binding protein, such as an antibody or an antibody -based binding protein, means that the binding protein is only capable of binding a single molecule of the antigen to which it specifically binds, and thus is not capable of antigen crosslinking.

[0160] “Percent (%) identity" refers to the extent to which two sequences (nucleotide or amino acid) have the same residue at the same positions in an optimal alignment. For example, “an amino acid sequence is X% identical to SEQ ID NO: Y” refers to % identity of the amino acid sequence to SEQ ID NO: Y and is elaborated as X% of residues in the amino acid sequence are identical to the residues of sequence disclosed in SEQ ID NO: Y.Generally, computer programs are employed for such calculations. Exemplary programs that compare and align pairs of sequences include ALIGN (Myers and Miller, 1988), FAST A (Pearson and Lipman, 1988; Pearson, 1990) and gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984). If different computer programs result in different alignments of two sequences, the "optimal" alignment is to be used for comparative purposes, which is the alignment that results in the highest % identity between the two sequences (i.e., the highest number of positions with the same residues at the same positions between the two sequences).

[0161] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0162] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0163] As used herein, “polypeptide,” which may be used interchangeably with “protein,” refers to a string of at least two amino acids attached to one another by a peptide bond. In some embodiments, a polypeptide may include at least 3-5 amino acids, each of which isattached to others by way of at least one peptide bond. Those of ordinary skill in the art will appreciate that polypeptides can include one or more “non-natural” amino acids or other entities that nonetheless are capable of integrating into a polypeptide chain. In some embodiments, a polypeptide may be glycosylated, e.g., a polypeptide may contain one or more covalently linked sugar moieties. In some embodiments, a single “polypeptide” (e.g., an antibody polypeptide) may comprise two or more individual polypeptide chains, which may in some cases be linked to one another, for example by one or more disulfide bonds or other means.

[0164] In some instances, the present disclosure refers to a molecule that is used as a “reference,” such as a “reference binding protein.” Generally, such reference molecules are identical to the molecule against which it is being compared except for a key aspect, e.g., presence or absence of an Fc modification.

[0165] As used herein, the phrase “reference level” generally refers to a level considered “normal” for comparison purposes, e.g., a level of an appropriate control. For example, in the context of half-life e.g. serum half-life) of a protein (e.g., a binding protein) a reference level may refer to the half-life of a “reference binding protein” as described herein.

[0166] As used herein, the phrase “specifically binds” or “selectively binds” to a target (e.g., APRIL), when referring to a binding protein as described herein, refers to a binding reaction by which the binding protein binds to the target with higher affinity, higher avidity and / or or longer duration than it binds to a structurally different target. In typical embodiments, the binding protein has an affinity of at least 5-fold, 6-fold, 7-fold, 8-fold, 9- fold, 10-fold, 20-fold, 25-fold, 50-fold, 100-fold, 1,000-fold, 10,000-fold, or greater by a specific target compared to an unrelated target when tested under the same affinity assay conditions. The term “specific binding,” “binds specifically to,” or “is specific to” a particular target, as used herein, may be presented, for example, by a molecule that has an equilibrium dissociation constant Kd for the target to which it binds, e.g., on the order of 10'5M, 10’6M, IO’7M, 10’8M, 10’9M, 10’10M, IO’11M, 10’12M, IO’13M, 10’14M, or 10’15M or less. In some embodiments, the binding protein (e.g., monoclonal antibody) binds to the target (e.g., APRIL) with affinity in the femtomolar range (e.g., 10‘15M). In some embodiments, a binding protein can specifically bind to an epitope on a target that is conserved between species (e.g., structurally conserved between species), e.g., conserved between human and non-human primate species (e.g. , structurally conserved between human and non-humanprimate species). In some embodiments, a binding protein may bind exclusively to a given target, e.g., exclusively to APRIL but not to other molecules.

[0167] The terms “subject,” “recipient”, “individual”, “host”, and “patient”, are used interchangeably herein and in some embodiments, refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory, zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys etc. In some embodiments, the mammal is human. None of these terms require the supervision of medical personnel.

[0168] As used herein, to “treat” a condition or “treatment” of the condition (e.g., the conditions described herein) is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. “Palliating” a disease, disorder, or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.

[0169] The terms “variable domain” and “variable region” are used interchangeably and refer to the portions of the antibody (or binding protein) 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 antigenbinding surface.

[0170] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0171] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.APRIL-Binding Proteins

[0172] In one aspect, provided are binding proteins that are capable of binding to APRIL (a proliferation inducing ligand (“APRIL-binding proteins”). In some embodiments, provided binding proteins are capable of binding to an epitope of human APRIL.

[0173] In some embodiments, APRIL-binding proteins of the disclosure are capable of binding to an epitope of human APRIL with ultra-high affinity, e.g., a Kd in the femtomolar (10-15M) range. In some embodiments, an APRIL-binding protein of the disclosure has an equilibrium dissociation constant Kd for APRIL in a range of 1 x 10’12M to IO15M, or 1 x 10'12M to 1 x 10’14M, or 5 x IO’12M to 5 x 1014M or 5 x IO’13M to 5 x 1014M.

[0174] In some embodiments, an APRIL-binding protein of the disclosure competes for binding to an epitope of human APRIL with an anti -APRIL antibody disclosed herein, e.g., an anti-APRIL antibody comprising CDR sequences, or VH / VL sequences, as set forth in any of Tables IA-IU. In embodiments, the APRIL-binding protein of the disclosure competes for binding to an epitope of human APRIL with an anti-APRIL antibody comprising CDRs, or VH / VL sequences, as set forth in any of Tables 1I-1U. In embodiments, the APRIL-binding protein of the disclosure competes for binding to an epitope of human APRIL with an anti- APRIL antibody comprising CDRs, or VH / VL sequences, as set forth in Table IS.

[0175] In some embodiments, APRIL binding proteins of the disclosure exhibit one, two, three, four or five of the following properties: (i) ultra-high affinity binding (e.g., femtomolar affinity) to APRIL; (ii) reduced (e.g., minimal) high molecular weight complex formation; (iii) reduced (e.g., minimal) TMDD in vivo,' (iv) a long plasma T1 / 2; and / or (v) reduced effector function(s) (e.g., Fc-mediated effector function(s)). In embodiments, an APRIL-bindingprotein of the disclosure competes for binding to an epitope of human APRIL with an anti- APRIL antibody disclosed herein (e.g., any of the embodiments set forth in the preceding paragraph) and further exhibits one, two, three, four or five of the aforementioned properties.

[0176] In some embodiments, an APRIL-binding protein of the disclosure exhibits at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% less (or lower) high MW complex formation compared to an existing APRIL-binding protein known in the art, such as any of the Reference Molecules set forth in Table 3.

[0177] In some embodiments, an APRIL-binding protein of the disclosure exhibits at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% less (or lower) TMDD in vivo compared to an existing APRIL-binding protein known in the art, such as any of the Reference Molecules set forth in Table 3.

[0178] In some embodiments, an APRIL-binding protein of the disclosure exhibits a T1 / 2 that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250% or 300% longer compared to an existing APRIL-binding protein known in the art, such as any of the Reference Molecules set forth in Table 3. In embodiments, the T1 / 2 of an APRIL-binding protein of the disclosure is at least 20 days, at least 25 days or at least 30 days.

[0179] In some embodiments, an APRIL-binding protein of the disclosure exhibits at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% less (or lower) Fc-mediated effector function compared to an existing APRIL-binding protein known in the art, such as any of the Reference Molecules set forth in Table 3.

[0180] In some embodiments, the binding proteins are antibodies or fragments thereof. In some embodiments, the antibodies or fragments thereof are monoclonal antibodies or fragments thereof. In some embodiments, the antibodies or fragments thereof are chimeric antibodies or fragments thereof. In some embodiments, the antibodies or fragments thereof are humanized antibodies or fragments thereof. In some embodiments, the antibodies or antigen-binding fragments are human antibodies.

[0181] Antigen-binding fragments may be, e.g., an scFv, an Fab, an scFab (single-chain Fab). As used herein, the term “scFv” is used in accordance with its common usage in the art to refer to a single chain in which the VH domain and the VL domain from an antibody are joined, typically via a linker. As used herein, the term “Fab fragment” is used in accordance with its common usage in the art. Fab fragments typically comprise an entire light chain (VLand CLI domains), the variable region domain of the heavy chain (VH), and the first constant domain of one heavy chain (CHI).

[0182] In some embodiments, provided APRIL-binding proteins comprise a heavy chain variable domain comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in a table selected from any of Tables 1A-1U. In some embodiments, provided APRIL-binding proteins further comprise a light chain variable domain comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 with sequences as shown in a table selected from any of Tables 1 A-1U.

[0183] In some embodiments, provided APRIL-binding proteins comprise a heavy chain variable domain with heavy chain variable sequences as shown in a table selected from any of Tables 1 A-1U. In some embodiments, provided APRIL-binding proteins comprise a heavy chain variable domain which is a variant of the heavy chain variable sequence shown in a table selected from any of Tables 1 A-1U, in that the heavy chain variable domain has (1) CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in a table selected from any of Tables 1A-1U and (2) an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the heavy chain variable domain sequence shown in a table selected from any of Tables 1 A-1U.

[0184] In some embodiments, provided APRIL-binding proteins comprise a heavy chain variable domain as described herein and further comprise a light chain variable region which has (1) CDR-L1, CDR-L2, and CDR-L3 with sequences as shown in a table selected from any of Tables 1A-1U and (2) an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the light chain variable domain sequence shown in the same table.

[0185] In some embodiments, provided APRIL-binding proteins comprise a heavy chain with an amino acid sequence as shown in a table selected from any of Tables 1 A-1U. In some embodiments, provided APRIL-binding proteins comprise a heavy chain with an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%identical to the amino acid sequence of a heavy chain sequence selected from any of Tables 1A-1U.

[0186] In some embodiments, provided APRIL-binding proteins comprise (1) a heavy chain with an amino acid sequence as shown in a table selected from any of Tables 1 A-1U and (2) a light chain with an amino acid sequence as shown in the same table. In some embodiments, provided APRIL-binding proteins comprise (1) a heavy chain with an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of a heavy chain sequence selected from any of Tables 1A-1U and (2) a light chain with an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of a light chain sequence shown in the same table.Table 1A. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IB. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable 1C. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable ID. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IE. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IF. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable 1G. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable 1H. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable II. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable 1J. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IK. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IL. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IM. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IN. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IO. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IP. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IQ. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable 1R. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IS. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable IT. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsTable 1U. Exemplary consensus heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsFc polypeptides

[0187] Binding proteins suitable for use in accordance with the present disclosure typically comprise an immunoglobulin Fc region. Fc regions typically comprise one or more Fc chains (e.g., Fc polypeptides, such as a first Fc polypeptide and a second Fc polypeptide). An IgG Fc polypeptide typically contains two constant heavy domains (CH2 and CH3) and a hinge region connected to the CH2 domain. Fc regions may typically comprise two Fc polypeptide which dimerize with one another; however, an Fc region may have a single Fc polypeptide or more than two Fc polypeptide, e.g., as may be present in some antibody formats.

[0188] Removal of C-terminal lysines by carboxypeptidases from the heavy chain is a commonly observed antibody modification, both upon recombinant expression of antibodies in mammalian cells, as well as in vivo in human serum (Cai et al. (2010) Biotechnol. Bioeng. Sep 9). Removal is often partial, resulting in a mixed population of antibodies with zero (K0), one (KI) or two (K2) C-terminal lysines. In particular, B-cell hybridomas produce mixtures of KO, KI and K2 molecules (Dick et al. (2008) Biotech. Bioeng. 100:1132).

[0189] In some embodiments, the Fc region of the binding protein comprises a lysine or another amino acid at the C-terminus. In some embodiments, the Fc region of the binding protein lacks one or more amino acids at the C-terminus, e.g., the binding protein comprises an Fc region comprising a human IgG sequence which lacks the C-terminal lysine (e.g., K447 in human IgGl) or the C-terminal “GK” sequence (e.g., G446 and K447 in human IgGl). In some embodiments, the binding protein further comprises an Fc region comprising a humanIgG sequence which lacks the C-terminal G446 (according to Kabat) of any of the sequences in Table 2A, but is otherwise identical to one of the aforesaid sequences.

[0190] Although a C-terminal lysine may be present in the corresponding coding sequence of the constant heavy chain region (e.g., a sequence encoding any of the constant region sequences shown in Table 2B), it may be cleaved off during manufacture or after administration (resulting in, e.g., a constant heavy chain sequence lacking the C-terminal lysine (e.g., K447 in human IgGl according to Kabat)). Accordingly, any of the binding proteins described above may comprise a human IgG sequence (e.g., any of the sequences shown in Tables 2A and 2B) containing a C-terminal lysine, a human IgG sequence lacking a C-terminal lysine, or a mixture thereof (e.g., a mixture of the same heavy chain constant sequence with and without a C-terminal lysine).

[0191] In some embodiments, the Fc region of the binding protein is originally encoded with a C-terminal lysine, but the C-terminal lysine is removed by a carboxypeptidase, e.g., in a production cell or in serum. In some embodiments, the Fc region of the binding protein is originally encoded without a C-terminal lysine and thus does not contain a C-terminal lysine to begin with. In some embodiments, the Fc region of the binding protein is originally encoded without a C-terminal “GK” sequence and thus does not contain a C-terminal “GK” sequence to begin with.

[0192] In some embodiments, binding proteins comprise an IgGl Fc region (e.g., human IgGl Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgGl Fc. In some embodiments, the wild type IgGl Fc is a human IgGl Fc, in which each Fc chain has an amino acid sequence of SEQ ID NO: 145. In some embodiments, binding proteins comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to that of an Fc chain within a wild-type IgGl Fc, e.g., a polypeptide having an amino acid sequence of SEQ ID NO: 145.

[0193] In some embodiments, binding proteins comprise an IgG2 Fc region (e.g., human IgG2 Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgG2 Fc. In some embodiments, the wild type IgG2 Fc is a humanIgG2 Fc, in which each Fc chain has an amino acid sequence of SEQ ID NO: 147. In some embodiments, binding proteins comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to that of an Fc chain within a wild-type IgG2 Fc, e.g., a polypeptide having an amino acid sequence of SEQ ID NO: 147.

[0194] In some embodiments, binding proteins comprise an IgG4 Fc region (e.g., human IgG4 Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgG4 Fc. In some embodiments, the wild type IgG4 Fc is a human IgG4 Fc, in which each Fc chain has an amino acid sequence of SEQ ID NO: 146. In some embodiments, binding proteins comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to that of an Fc chain within a wild-type IgG4 Fc, e.g., a polypeptide having an amino acid sequence of SEQ ID NO: 146.

[0195] In some embodiments, Fc regions comprise a means for enhancing the half-life of the binding protein. Examples of such means include, but are not limited, certain half-life extending mutations or sets of mutations as described below in the “Fc mutations” section.

[0196] In addition to or alternative to Fc mutations, other approaches known in the art for enhancing the half-life of a binding protein can be used to increase the T 1 / 2 of an APRIL- binding protein of the disclosure, such as approaches involving conjugation of a chemical moiety to the APRIL-binding protein to thereby enhance its half-life (reviewed in, for example, Wijesinghe et al. (2022) PLoS One 17:e0255753; Binder et al. (2025) Expert Opin. Biol. Therap. 25:93-1 18). Such approaches include, but are not limited to, conjugation of polyethylene glycol (PEG) chains to the binding protein (PEGylation) (see e.g., Batra et al. (2012) PLoS One 7:e50028; Kumar et al. (2020) Curr. Top. Med. Chem. 20:337-348; Xu et al. (2023) Int. J. Mol. Sci. 24:3387), modification of the binding protein by glycosylation (see e.g., Ludwig et al. (2022) MAbs 14:2095704; Bellavita et al. (2023) Pharmaceuticals (Basel) 16:439), conjugation with albumin (see e.g., Li et al. (2020) MedComm. 5:e557; Go et al. (2024) J. Biol. Eng. 18:23; Mester et al. (2025) PNAS Nexus 4:pgaf042), modification with a lipid moiety (lipidation)(see e.g., Gomez-Solar et al. (2023) Eur. J. Med. Chem. 262:115876; Myskova et al. (2023) Drug. Deliv. 30:2284685) and modification with Proline-Alanine-richsequences (PASylation)(see e.g., Ahmadpour et al. (2018) Curr. Drug Deliv. 15:331-341; Mazaheri et al. (2020) Sci. Rep. 10: 18464).

[0197] Additionally or alternatively, the Fc region of an APRIL-binding protein of the disclosure can be modified to alter (e.g., inhibit or enhance) one or more effector functions of the protein. For example, it has been demonstrated in the art that afucosylated antibodies exhibit enhanced antibody-dependent cellular cytotoxicity (ADCC) activity compared to fucosylated antibodies (see e.g., Satoh et al. (2006) Exp. Opin. Biol. Therap. 6: 1161-1 173). Accordingly, in some embodiments, an APRIL-binding protein of the disclosure has an afucosylated Fc region (e.g., to enhance ADCC activity). Approaches for preparing afucosylated Fc regions are well-established in the art, including but not limited to expression of the antibody in CHO Led 3 cells, which are naturally deficient in fucosylation ability, expression of the antibody in host cells in which the FUT8 gene or the GDP-fucose transporter (GFT) gene has been inactivated, biochemical inhibition of fucosylation and chemoenzymatic remodelling strategies (see e.g., Pereira et al. (2018) MAbs 10:693-711 for a review of afucosylation approaches).Fc mutations

[0198] In certain embodiments, Fc regions are modified (e.g., substituted) at one or more amino acid residues.

[0199] In some embodiments, the Fc region comprises one or more modifications which modify binding to Fc-gamma receptors, e.g., by promoting selective binding, reducing binding, or enhancing binding thereto.

[0200] In certain embodiments, modifications to Fc regions alter the half-life of a molecule (e.g., binding protein) which comprises the Fc region by altering (e.g., enhancing) binding to an Fc receptor such as the neonatal Fc receptor (FcRn.) For example, in some embodiments, the Fc region is modified to enhance the half-life of the molecule (e.g., binding protein) which comprises the Fc region. Non-limiting examples of half-life-enhancing mutations or sets of mutations include, e.g., M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

[0201] In some embodiments, modifications to Fc regions prevent Fab arm (e.g., IgG4 Fab arm) exchange. An example of such a modification in the context of an IgG4 Fc region is the S228P mutation.

[0202] In some embodiments, modifications to Fc regions reduce or abrogate effector functions, e.g., Fey receptor-mediated effector functions. Non-limiting examples of effector-reducing mutations or sets of mutations include, e.g., aglycosylation mutations (e.g., N297A or N297Q or N297G), L234A / L235A (for IgGl Fc regions), H268Q / V309L / A330S / P331S (for IgG2 Fc regions), and V234A / G237A / P238S / H268A / V309L / A330S / P331S (for IgG2 Fc regions). In some embodiments, effector function is reduced by modifying the attached sugar structures. Non-limiting examples of effector-reducing sugar modifications include increasing sialylation or galactosylation of the sugar chains.

[0203] In some embodiments, modifications to Fc regions enhance Fey receptor- mediated effector functions. Non-limiting examples of FcyRIIIa effector-enhancing mutations or sets of mutations include, e.g., F243L / R292P / Y300L / V305I / P396L, S298A / E333A / K334A, S239D / I332E, S239D / I332E / A330L, andL234Y / L235Q / G236W / S239M / H268D / D270E / S298A in one Fc polypeptide and D270E / K326D / A330M / K334E in another Fc polypeptide. In some embodiments, modification of the sugar chains (e.g., reduction or removal of fucosylation) can increase the affinity to FcyRIIIa resulting in enhanced ADCC activity.

[0204] In some embodiments, modifications to Fc regions enhance antibody -dependent cellular phagocytosis (ADCP). A non-limiting example of an ADCP-enhancing set of mutations is G236A / S239D / I332E. In some embodiments, modification of the structures of the sugar chains (e.g., reduction or removal of fucosylation) can result in increased ADCP activity.

[0205] In some embodiments, modifications to Fc regions enhance complementdependent cytotoxicity (CDC) and / or binding to complement protein Clq. Non-limiting examples of an CDC-enhancing and / or Clq-binding -enhancing sets of mutations include, e.g., K326W / E333S, S267E / H268F / S324T, and E345R / E430G / S440Y. In some embodiments, modification of the structures of the sugar chains (e.g., reduction or removal of fucosylation) can result in increased CDC activity.

[0206] In some embodiments, modifications to Fc regions enhance co-engagement with antigens and Fey receptors. Non-limiting examples of co-engagement -enhancing sets of mutations include, e.g., S267E / L328F and N325S / L328F.

[0207] Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0208] Amino acid sequences of exemplary Fc polypeptide sequences are provided in Tables 2A-2B.Table 2A. Exemplary Fc Polypeptide SequencesTable 2B. Exemplary Fc polypeptide sequences

[0209] In some embodiments, the binding protein comprises an Fc region comprising one or more modifications in SEQ ID NO: 145 (hlgGl). In some embodiments, the binding protein comprises an Fc region comprising one or more modifications in SEQ ID NO: 146 (hIgG2). In some embodiments, the binding protein comprises an Fc region comprising one or more modifications in SEQ ID NO: 147 (hIgG4). In some embodiments, the Fc region comprises an Fc polypeptide whose amino acid sequence has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 145-147. In some embodiments, the Fc region comprises an amino acid sequence according to any one of SEQ ID NOs: 145-147.

[0210] In certain embodiments, the binding protein comprises an Fc region (“modified Fc region’’) with at least one amino acid modification relative to a wild type Fc region. Binding proteins with a modified Fc region may comprise mutations in one Fc polypeptide, or in multiple Fc polypeptide (e.g., when two or more Fc polypeptide are present). Within a binding protein with modifications in multiple Fc polypeptide, the modifications on each Fc polypeptide may be the same or different. In some embodiments the modified Fc region comprises a half-life extending mutation or set of mutations, e.g., M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0211] In some embodiments, the modified Fc region comprises a modification selected from the group consisting of: S298A, E333A, K334A, K326A, F243L, R292P, Y300L, V305I, P396L, F243L, R292P, Y300L, L235V, P396L, F243L, S239D, I332E, A330L, S267E, L328F, D265S, S239E, K326A, A327H, G237F, K326E, G236A, D270L, H268D, S324T, L234F, N325L, V266L, S267D, K214R, D356E, L358M, and combinations thereof. In some embodiments, the modified Fc region comprises a modification selected from the group consisting of S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311 V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, N434W, and combinations thereof.

[0212] In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions selected from the group consisting of: L234A / L235A;V234A / G237A; L235A / G237A / E318A; S228P / L236E; H268Q / V309L / A330S / A331S; C220S / C226S / C229S / P238S; C226S / C229S / E3233P / L235V / L235A; L234F / L235E / P33 IS; C226S / P230S; L234A / G237A; L234A / L235A / G237A; Q311R / M428L;L234A / L235A / P329G; K214R / D356E / L358M; and combinations thereof.

[0213] In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS);M252Y / S254T / T256E (YTE); T250Q / M428L; T307A / E380A / N434A; T256D / T307Q (DQ); T256D / T307W (DW); M252Y / T256D (YD); T307Q / Q311V / A378V (QVV);T256D / H285D / T307R / Q311V / A378V (DDRVV); L309D / Q311H / N434S (DHS); S228P / L235E (SPLE); L234A / L235A (LALA); M428L / N434A (LA); L234A / G237A (LAGA); L234A / L235A / G237A (LALAGA); L234A / L235A / P329G (LALAPG); H433K / N434F (KF); N297A / YTE; D265A / YTE; LALA / YTE; LAGA / YTE;LALAGA / YTE; LALAPG / YTE; N297A / LS; D265A / LS; LALA / LS; LAGA / LS; LALAGA / LS; LALAPG / LS; N297A / DHS; D265A / DHS; LALA / DHS; LAGA / DHS; LALAGA / DHS; LALAPG / DHS; SP / YTE; SPLE / YTE; SP / LS; SPLE / LS; SP / DHS; SPLE / DHS; N297A / LA; D265A / LA; LALA / LA; LAGA / LA; LALAGA / LA; LALAPG / LA; N297A / N434A; D265A / N434A; LALA / N434A; LAGA / N434A; LALAGA / N434A; LALAPG / N434A; N297A / N434W; D265A / N434W; LALA / N434W; LAGA / N434W; LALAGA / N434W; LALAPG / N434W; N297A / DQ; D265A / DQ; LALA / DQ; LAGA / DQ; LALAGA / DQ; LALAPG / DQ; N297A / DW; D265A / DW; LALA / DW; LAGA / DW;LALAGA / DW; LALAPG / DW; N297A / YD; D265A / YD; LALA / YD; LAGA / YD;LALAGA / YD; LALAPG / YD; N297A / QVV; D265A / QVV; LALA / QVV; LAGA / QVV, LALAGA / QVV: LALAPG / QW: N297A / DDRVV; D265A / DDRVV; LALA / DDRVV; LAGA / DDRVV; LALAGA / DDRVV; LALAPG / DDRVV; SP / Q311R / M428L;SPLE / Q311R / M428L; N297A / Q311R / M428L; D265A / Q311R / M428L; LALA / Q311R / M428L; LAGA / Q311R / M428L; LALAGA / Q311R / M428L;LALAPG / Q311R / M428L; and combinations thereof. In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS), M252Y / S254T / T256E (YTE), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS). In some embodiments, the modified Fc region comprises M428L / N434S (LS) (e.g., SEQ ID NO: 163, SEQ ID NO: 165, SEQ ID NO: 180, SEQ ID NO: 187, SEQ ID NO: 467, SEQ ID NO: 484, or SEQ ID NO: 491) modifications. In some embodiments, the modified Fc region comprises M252Y / S254T / T256E (YTE) (e.g., SEQ ID NO: 156, SEQ ID NO: 177, SEQ ID NO: 186, SEQ ID NO: 443, SEQ ID NO: 460, SEQ ID NO: 481, SEQ ID NO: 490. or SEQ ID NO: 562) modifications.

[0214] In some embodiments, binding proteins include modifications to improve their ability to mediate effector function. Such modifications are known in the art and include afucosylation, or engineering of the affinity of the Fc region towards an activating receptor, mainly FCGR3a for antibody -dependent cellular cytotoxicity (ADCC), and towards Clq for complement-dependent cytotoxicity (CDC).

[0215] In some aspects, a binding protein provided herein comprises an Fc region (e.g., an IgGl Fc region) with reduced fucose content at position Asn 297 (EU numbering) compared to a naturally occurring Fc region. Such Fc regions are known to confer improved ADCC activity to the binding proteins which comprise them. In some aspects, such binding proteins do not comprise any fucose at position Asn 297.

[0216] In some embodiments, the binding proteins described herein include modifications to decrease their ability to mediate effector function. Such modifications are known in the art and include increased sialylation, or decreasing the affinity of the Fc region towards an activating receptor, mainly FCGR3a for antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, a binding protein provided herein comprises an Fc region (e.g., an IgGl Fc region) with increased sialyl content at position Asn 297 (EU numbering) compared to a naturally occurring Fc region.

[0217] In some embodiments, the binding protein comprises an Fc region with one or more amino acid substitutions which improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of an Fc polypeptide. In some embodiments, a binding protein provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330.

[0218] In some embodiments, the binding protein further comprises an Fc region comprising a human IgG sequence selected from the group consisting of any one of SEQ ID NOs: 145-567. In some embodiments, the Fc region comprises an Fc polypeptide whose amino acid sequence has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 145-567.

[0219] In some embodiments, the binding protein comprises an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such binding protein variants may have improved CDC function.

[0220] In some embodiments, the binding protein comprises one or more alterations that improve or diminish Clq binding and / or CDC.

[0221] In certain embodiments, the binding protein comprises an Fc region with one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of binding protein half-life, ADCC activity, ADCP activity, or CDC activity compared with a comparable binding protein whose Fc region lacks the one or more substitutions. In certain embodiments, the one or more amino acid substitutions results in increased binding protein half-life at pH 6.0 compared to a binding protein comprising a wild-type Fc region. In certain embodiments, the binding protein has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8- fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9- fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold. 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold. 1.45- fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to a binding protein comprising a wild-type Fc region.

[0222] In certain embodiments, the binding protein comprises an Fc region which comprise one or more amino acid substitutions, wherein the one or more substitutions resultin a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared to a comparable binding protein whose Fc region lacks the one or more substitutions.

[0223] In certain embodiments, the Fc region binds an Fey Receptor selected from the group consisting of: FcyRl, FcyRlla, FcyRIlb, FcyRIlc, FcyRllla, and FcyRllIb. In certain embodiments, the Fc region binds an Fey Receptor with higher affinity at pH 6.0 compared to a binding protein comprising a wild-type Fc region.

[0224] In some embodiments, the binding protein has an extended half-life (i.e., serum half-life) relative to the half-life of a reference binding protein. In some embodiments, the binding protein has a half-life of at least about 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks. In some embodiments, the binding protein has a half-life of more than 52 weeks. In some embodiments, the binding protein has a half-life of at least about 14, 28, 42, 56, 70, 84, 96, or more than 96 days. In some embodiments, provided binding proteins comprise a half-life of at least about 25, about 26, about 27, about 28, about 29 or about 30 days. In some embodiments, provided binding proteins comprise a half-life in a range of about 20 days to about 30 days, about 20 days to about 29 days, about 20 days to about 28 days, about 20 days to about 27 days, about 20 days to about 26 days, or about 20 days to about 25 days. In some embodiments, provided binding proteins comprise a half-life in a range of about 21 days to about 30 days, about 21 days to about 29 days, about 21 days to about 28 days, about 21 days to about 27 days, about 21 days to about 26 days, or about 21 days to about 25 days. In some embodiments, provided binding proteins comprise a half-life in a range of about 22 days to about 30 days, about 22 days to about 29 days, about 22 days to about 28 days, about 22 days to about 27 days, about 22 days to about 26 days, or about 22 days to about 25 days. In some embodiments, provided binding proteins comprise a half-life in a range of about 23 days to about 30 days, about 23 days to about 29 days, about 23 days to about 28 days, about 23 days to about 27 days, about 23 days to about 26 days, or about 23 days to about 25 days. In some embodiments, provided binding proteins comprise a half-life in a range of about 24 days to about 30 days, about 24 days to about 29 days, about 24 days to about 28 days, about 24 days to about 27 days, about 24 days to about 26 days, about 24 days or about 25 days. In some embodiments, provided binding proteins comprise a half-life in a range of about 14 days to about 96 days, about 14 days to about 84 days, about 14 days to about 70 days, about 14 days to about 56 days, about 14 days to about 42 days, about 14 days to about 28 days, of about 28 days to about 96 days, about 28 days to about 84 days, about 28 days to about 70 days, about28 days to about 56 days, about 28 days to about 42 days, of about 42 days to about 96 days, about 42 days to about 84 days, about 42 days to about 70 days, or about 42 days to about 56 days. In some embodiments, provided binding proteins comprise a half-life of at least about 50 days, at least about 55 days, at least about 60 days, at least about 65 days, at least about 70 days, at least about 75 days, at least about 80 days, at least about 85 days, or at least about 90 days. In some embodiments, the provided binding proteins comprise a half-life of about 50 days, about 55 days, about 60 days, about 65 days, about 70 days, about 75 days, about 80 days, about 85 days, or about 90 days. Methods of measuring half-life are known in the art. In some embodiments, the half-life is measured in a non-human primate. In some embodiments, the half-life is measured in a human. In some embodiments, the half-life is measured following intravenous administration. In some embodiments, the half-life is measured following subcutaneous administration.

[0225] In some embodiments, the binding protein has a half-life that is at least 20% longer than a reference binding protein. In some embodiments, the reference binding protein comprises the same complementarity determining regions and variable regions but different Fc regions, or a reference binding protein which is bivalent and monospecific but has the same complementarity determining regions and variable regions. In some embodiments, the half-life of the binding protein is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% longer than the half-life of the reference binding protein. In some embodiments, the half-life of the binding protein comprises is longer than the half-life of the reference binding protein by at least 2-fold, at least 3-fold, or at least 4- fold. In some embodiments, the half-life of provided binding proteins is longer than the halflife of the comparator antibody by at least 2-fold, at least 3-fold, at least 4-fold, at least 5- fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold.Reference Molecules

[0226] In certain embodiments, APRIL-binding proteins disclosed herein are compared against a reference molecule (e.g., for APRIL-binding activity and / or other functional activity, such as ability to block interaction between TACI or BCMA). In some embodiments, the reference molecule is an anti-APRIL antibody (e.g., Reference Molecule 1 or 2 as described in Table 3). In some embodiments, the reference molecule is an Fc fusion protein, e.g., a TACI-Fc fusion protein (e.g., Reference Molecule 3 or 4 as described in Table 3). Insome embodiments, the reference molecule is a reference molecule selected from Reference Molecule 1, 2, 3, or 4, whose characteristics such as sequences are shown in Table 3.Table 3. Characteristics (e.g., sequences) of certain reference moleculesPharmaceutical Compositions

[0227] The present disclosure also includes pharmaceutical compositions that contain therapeutically effective amounts of the APRIL-binding proteins disclosed herein. Compositions can be formulated for use in a variety of drug delivery systems. One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation. Suitable formulations for use in the present disclosure are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed., 1985. For a brief review of methods for drug delivery, see, e.g.. Langer (Science 249: 1527- 1533, 1990).

[0228] In some embodiments, a pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, 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 (such as glycine, glutamine, asparagine, arginine 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)); complexing agents (such as caffeine, polyvinylpyrrolidone, betacyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); 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, triton, tromethamine, lecithin, cholesterol, tyloxapal); 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)).

[0229] In some embodiments, a pharmaceutical composition is citrate -free.

[0230] In some embodiments, a pharmaceutical composition may contain nanoparticles, e.g., polymeric nanoparticles, liposomes, or micelles.

[0231] In some embodiments, a pharmaceutical composition may contain a sustained- or controlled-delivery formulation. Techniques for formulating sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Sustained-release preparations may include, e.g., porous polymeric microparticles or semipermeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained release matrices may include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L- glutamate, poly (2-hydroxyethyl-methacrylate), ethylene vinyl acetate, or poly-D(-)-3- hydroxybutyric acid. Sustained release compositions may also include liposomes that can be prepared by any of several methods known in the art.

[0232] Pharmaceutical compositions containing a binding protein disclosed herein can be presented in a dosage unit form and can be prepared by any suitable method. A pharmaceutical composition should be formulated to be compatible with its intended route of administration, as discussed further herein in the “Methods of Treatment” section.

[0233] Useful formulations can be prepared by methods known in the pharmaceutical art. For example, see Remington ’s Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. In some embodiments, the formulation for parenteral administration is citrate-free.

[0234] 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 bea solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.

[0235] 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.

[0236] 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.

[0237] A polyol, which acts as a tonicifier and may stabilize the binding protein, may also be included in the formulation. The polyol is added to the formulation in an amount which may vary with respect to the desired isotonicity of the formulation. In some embodiments, the aqueous formulation is isotonic. The amount of polyol added may also be altered with respect to the molecular weight of the polyol. For example, a lower amount of a monosaccharide (e.g., mannitol) is added, compared to a disaccharide (such as trehalose). In some embodiments, the polyol which is used in the formulation as a tonicity agent is mannitol.

[0238] 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 poloxamers (e.g., poloxamer 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) sorbitanmonooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th edi., 1996).

[0239] In 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, theliquid formulation may also include one or more of a buffering agent, a surfactant, and a preservative.

[0240] 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.

[0241] 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.

[0242] A preservative may be optionally added to the formulations herein to reduce bacterial action. The addition of a preservative may, for example, facilitate the production of a multi-use (multiple -dose) formulation.

[0243] The binding protein may be lyophilized to produce a lyophilized formulation including the proteins and a lyoprotectant. The lyoprotectant may be sugar, e.g., disaccharides. In some embodiments, the lyoprotectant is sucrose or maltose. The lyophilized formulation may also include one or more of a buffering agent, a surfactant, a bulking agent, and / or a preservative.

[0244] 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.

[0245] Methods of Preparing APRIL-Binding Proteins

[0246] The APRIL-binding proteins of the disclosure can be prepared by standard recombinant methods, such as by expressing a nucleic acid(s) encoding the APRIL-binding protein in host cells such that the APRIL-binding protein is produced by the host cells. The APRIL-binding protein can be recovered from the host cells and / or the culture supernatant of the host cells. Example 2 describes a non-limiting exemplary embodiment of a method of preparing an APRIL-binding protein of the disclosure. In embodiments, the method ofpreparing an APRIL-binding protein of the disclosure comprises incorporating one or more nucleic acids encoding an APRIL-binding protein of the disclosure into an expression vector, introducing the expression vector(s) into a host cell, culturing the host cell such that the APRIL- binding protein is expressed by the host cell and recovering the APRIL-binding protein from the host cell or culture supernatant thereof. In embodiments, the APRIL-binding protein comprises an antibody heavy chain and an antibody light chain, wherein nucleic acid encoding the heavy chain and nucleic acid encoding the light chain can be incorporated into the same or different expression vectors. In embodiments, the host cell is a eukaryotic host cell, such as a mammalian host cell (e.g., CHO cells), and the expression vector is a eukaryotic expression vector, such as a mammalian expression vector. Following expression, the APRIL-binding protein can be isolated (e.g., purified) using standard methods well established in the art.Methods of Treatment

[0247] Described herein, in certain embodiments, are methods of treating a subject in need thereof, the method comprising a step of administering to the subject an effective amount of an APRIL-binding protein or a pharmaceutical composition as disclosed herein.

[0248] The method of treatment can be used in a variety of diseases and disorders in which inhibition of APRIL function (e.g., APRIL blockade) can be therapeutically beneficial, examples of which include but are not limited to diseases or disorders characterized by overexpression of APRIL, overexpression of IgA, overexpression of IgM or overexpression of IgE.

[0249] In embodiments, the method of treatment is used for treatment of an autoimmune or inflammatory disease or disorder. Examples of such autoimmune or inflammatory diseases and disorders include, but are not limited to, IgA nephropathy, myasthenia gravis, systemic lupus erythematosus, membranous glomerulonephritis, Sjbgrens disease, lupus nephritis, immune thrombocytopenia, acquired (autoimmune) hemolytic anemia, cold agglutinin disease (CAD), autoimmune hepatitis, multiple sclerosis, pemphigus vulgaris, rheumatoid arthritis, IgM-mediated diseases (e.g., multifocal motor neuropathy (“MMN”), anti-MAG (myelin-associated glycoprotein) neuropathy, hidradenitis suppurativa, ANCA- associated vasculitis (AAV), IgA Vasculitis, Minimal Change Disease (MCD), Focal Segmental Glomerulosclerosis (FSGS), Primary Nephrotic Syndrome, Systemic Sclerosis, Antineutrophil Cytoplasmic Antibody-associated Vasculitis, Nephritis, anti-NMDAR andanti-LGIl encephalitis, Connective tissue disease-associated thrombocytopenia and Celiac Disease.

[0250] In embodiments, the method of treatment is used for treatment of an allergic disease or disorder. Examples of such allergic diseases or disorders include food allergies, respiratory allergies, chemical allergies, asthma, hives, atopic dermatitis (eczema) and contact dermatitis.Subjects

[0251] In certain embodiments, the subject is a mammal, such as a primate. In some embodiments, the subject is human.

[0252] In embodiments, the subject is suffering from, exhibits at least one symptom of, is diagnosed with, and / or is identified as at risk of an autoimmune disease or disorder or an inflammatory disease or disorder. Examples of such autoimmune or inflammatory diseases and disorders include, but are not limited to, IgA nephropathy, myasthenia gravis, systemic lupus erythematosus, membranous glomerulonephritis, Sjogrens disease, lupus nephritis, immune thrombocytopenia, acquired (autoimmune) hemolytic anemia, cold agglutinin disease (CAD), autoimmune hepatitis, multiple sclerosis, pemphigus vulgaris, rheumatoid arthritis, and IgM-mediated diseases (e.g., multifocal motor neuropathy (“MMN”), anti -MAG (myelin-associated glycoprotein) neuropathy, hidradenitis suppurativa, ANCA-associated vasculitis (AAV), IgA Vasculitis, Minimal Change Disease (MCD), Focal Segmental Glomerulosclerosis (FSGS), Primary Nephrotic Syndrome, Systemic Sclerosis, Antineutrophil Cytoplasmic Antibody-associated Vasculitis, Nephritis, anti-NMDAR and anti-LGIl encephalitis, Connective tissue disease-associated thrombocytopenia and Celiac Disease.

[0253] In embodiments, the subject is suffering from, exhibits at least one symptom of, is diagnosed with, and / or is identified as at risk of an allergic diseases or disorders. Examples of such allergic diseases or disorders include food allergies, respiratory allergies, chemical allergies, asthma, hives, atopic dermatitis (eczema) and contact dermatitis.

[0254] In some embodiments, the subject is suffering from, exhibits at least one symptom of, is diagnosed with, and / or is identified as at risk of IgAN. In some embodiments, the subject has IgAN. In some embodiments, the subject has proteinuria (e.g., albuminuria), e.g., at levels of greater than or equal to about 0.5 g / day.Routes of administration

[0255] In certain embodiments, the step of administering comprises systemic administration. In certain embodiments, systemic administration comprises parenteral administration, e.g., intravenous administration, intraarterial administration, intraperitoneal administration, subcutaneous administration, or intradermal administration. In some embodiments, systemic administration comprises enteric administration, e.g., trans- gastroenteric administration or oral administration.

[0256] In some embodiments, the step of administering comprises intravenous administration. In some embodiments, the step of administering comprises subcutaneous administration.

[0257] Combination Treatments

[0258] In embodiments, a method of treatment of the disclosure comprising administering to a subject an effective amount of an APRIL-binding protein, or pharmaceutical composition thereof, as disclosed herein, further comprises administering one or more additional agents to the subject, such as one or more additional therapeutic agents that are suitable for treating the subject's disease or disorder. In an embodiment, the APRIL-binding protein and additional agent(s) are administered concurrently. In another embodiment, the subject is treated with the additional agent(s) prior to treatment with the APRIL-binding protein. In another embodiment, the subject is treated with the additional agent(s) subsequent to treatment with the APRIL-binding protein.

[0259] In embodiments, the subject has an autoimmune, inflammatory or allergic disease or disorder and the subject is treated with one or more additional agents that are standard of care for treatment of the disease or disorder. Non-limiting examples of additional agents used as standard of care for autoimmune, inflammatory or allergic diseases and disorders include corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone, fluticasone, dexamethasone, budesonide), immunosuppressive agents (e.g., cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil), B cell depletion therapy (e.g., anti-CD20 therapy, such as with rituximab), anti-IgE therapy (e.g., omalizumab, ligelizumab), and anti-IL-5 therapy (e.g., mepolizumab for severe eosinophilic asthma).

[0260] In embodiments, an APRIL-binding protein of the disclosure can be used in combination with an agent that is a BAFF antagonist. Non-limiting examples of types of BAFF antagonists include fusion proteins such as BAFF-Trap (see e.g., Yu et al. (2021) Mol. Immunol. 129:1-11), anti-BAFF monoclonal antibodies such as belimumab (see e.g., Zhang et al. (2022) Front. Immunol. 13:977377), anti-BAFF receptor monoclonal antibodies such as ianalumab (see e.g., Cuker et al. (2023) Blood 142:5427) and blisibmod, a peptibody BAFF antagonist (see e.g., Stohl et al. (2015) Arthritis Res. Therap. 17:215).

[0261] In embodiments, the subject has IgAN and the subject is treated with an APRIL- binding protein of the disclosure in combination with one or more additional agents used in the treatment of IgAN, non-limiting examples of which include corticosteroids, immunosuppressive agents, renin-angiotensin-aldosterone system (RAAS) inhibitors such as angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril, enalapril, ramipril), angiotensin-receptor blockers (ARBs)(e.g., losartan, candesartan, valsartan) and direct renin inhibitors (e.g., aliskiren), sodium glucose cotransporter 2 (SGLT2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), endothelin type A receptor antagonists (e.g., sparsentan, atrasentan, zibotentan), and complement inhibitors (e.g., CFB inhibitors such as iptacopan, CFD inhibitors such as danicopan, C5aRl inhibitors such as avacopan, C5 inhibitors such as eculizumab, ravulizumab, avacincaptad pegol, pozelimab, zilucoplan and crovalimab-akkz, C3 inhibitors such as pegcetacoplan, Clr / s inhibitors such as cinryze, berinert and ruconest, and Cis inhibitors such as sutimlimab).Outcomes

[0262] In many embodiments, methods disclosed herein result in a measurable improvement in the subject, e.g., in amelioration or resolution of symptoms. For example, such improvement may include an improvement in a clinical score or a score from a survey or questionnaire associated with, or suitable for assessing the autoimmune or inflammatory disease being treated.

[0263] In some embodiments, methods disclosed herein result in an outcome selected from the group consisting of: a reduction in proteinuria levels, a reduction in IgA immune complex formation and / or immune complex-mediated injury, a reduction in GdlgAl complex formation, a reduction in hematuria, preservation of eGFr, stabilization of eGFr, a slower rate of decline of eGFr, a decreased risk of end stage kidney disease, blood pressure control, a reduction in glomerular hyperfiltration, ameliorated impact of proteinuria on thetubulointerstitium, reduction in cardiovascular risk, and combinations thereof. In some embodiments, methods disclosed herein result in proteinuria levels of less than about 0.5 g / day, less than about 0.4 g / day, or less than about 0.3 g / day.EXAMPLESExample 1: Generation of anti-huAPRIL antibodies

[0264] Alloy ATX-Gx mice expressing chimeric antibodies with fully-human variable regions were immunized with recombinant human APRIL (huAPRIL) protein and / or DNA encoding huAPRIL. During immunizations, the serum was used to measure titers against huAPRIL by ELISA.B-Cell Isolation

[0265] Plasma cells from immunized mice were cultured as single cells and supernatants were screened for binding to recombinant huAPRIL protein to identify anti-huAPRIL- antibody producing cells. Total RNA was collected from plasma cells of interest to generate cDNA, and heavy and light variable regions were PCR amplified and sequenced.

[0266] Exemplary clones generated from this method include clones 114, 122, 151, 107, 156, 157, 205, and 199, whose characteristic sequences are shown in Tables 1A-1H.Phage Generation

[0267] Alternatively, total RNA was extracted from lymph node cells in immunized mice and variable heavy and light chains were PCR amplified. Variable heavy and light chains were recombined into a phagemid vector to generate phage libraries. The phage libraries were screened against recombinant huAPRIL to identify clones with high affinity to huAPRIL. Additional secondary screenings were conducted with the high affinity binding clones to identify clones that avoided high molecular weight complex formation, clones that exhibited reduced TMDD and clones that both avoided high molecular weight complex formation and exhibited reduced TMDD.

[0268] Exemplary clones generated from this method include clones 702, 705, 722, 731, 733, 735, 736, 739, 740, 741, 743, and 753, whose characteristic sequences are shown in Tables 1I-1T, respectively.Example 2: Production and purification of recombinant anti-huAPRIL antibodies

[0269] To produce fully-human anti-huAPRIL antibodies, DNA sequences encoding heavy and light variable regions of plasma cells of interest were recombinantly assembled into separate mammalian cell expression vectors with a mutant human IgGl constant region (hlgGl-LALA / YTE; SEQ ID NO: 159) and wild-type human IgK constant region, respectively. ExpiCHO cells were transiently transfected and supernatants containing antibodies were harvested after up to 14 days. Antibodies were purified with HiTrap™ MabSelect SuRe™ Protein A (Cytiva) and polished by size-exclusion chromatography with HiLoad™ 26 / 200 Superdex™ 200 pg (GE Healthcare).Example 3: Determination of antibody affinity to huAPRIL and cyAPRIL

[0270] Binding affinity (KD) of antibodies to huAPRIL or cynomolgus APRIL (cyAPRIL) was determined by surface plasmon resonance using Biacore 8K+ (FIGs. 1A-1D; Table 4). Briefly, a CM5 Series S sensor chip functionalized with anti-human IgG Fc or anti-mouse IgG Fc antibody by amine coupling was used to capture antibodies at 0.25 pg / mL.Subsequently, titrated huAPRIL or cyAPRIL were injected at 10 pL / min. The chip was regenerated with 10 mM glycine pH 1.5 between runs.Table 4

[0271] The results demonstrated that the antibodies exhibit high binding affinity for huAPRIE, with some antibodies binding to huAPRIL with an affinity in the femtomolar range.Example 4: Blocking activity of anti-huAPRIL antibodies

[0272] Anti-huAPRIL antibodies were assessed for their ability to block huAPRIL-huTACI or huAPRIL-huBCMA interaction by ELISA. Plates were coated with huTACI-Fc or huBCMA-Fc, and huAPRIE-His-FEAG preincubated with titrated anti-huAPRIE antibodies was added to the plates. huAPRIL bound to huTACI or to huBCMA was detected with anti- FLAG-HRP. Nonlinear regression was performed on optical density (OD) at A450 to determine IC50 (FIGs. 2A-2D; Table 5). In FIGs. 2A-2D, results from experiments conducted using Reference Molecules 1, 2, 3, and / or 4 (which have sequences as shown in Table 3) are shown for comparison.Table 5TACI BCMAClone IC50 (nM) IC50 (nM)107 1.857 1.836114 0.7151 1.744122 1.116 2.008151 0.8561 1.527156 0.706 1.317157 0.6847 1.336199 0.9734 1.263205 0.6561 1.593702 1.303 2.004705 1.237 2.026722 1.542 2.109743 3.367 2.712Example 5: Functional activity of anti-huAPRIL antibodies in huTACI and huBCMA reporter assay

[0273] Anti-huAPRIL antibodies were assessed for their functional blockade of the huAPRIL-huTACI or huAPRIL-huBCMA interaction using huTACI-NFKB-Luc or huBCMA-NFKB-Luc cells that express luciferase reporter driven by NFKB under huAPRIL stimulation. IIUTACI-NFKB-LUC or huBCMA-NFicB-Luc cells were incubated with huAPRIL at ECso and titrated anti-huAPRIL antibodies for 5 hours (huTACI) or overnight (huBCMA), and ONE-Glo™ reagent was added to quantify luminescence. Nonlinear regression was performed on luminescence values to determine IC50 (FIGs. 3A-3D; Table 6). In FIGs. 3A- 3D. results from experiments conducted using Reference Molecules 1, 2, 3. and / or 4 are shown for comparison.Table 6TACI BCMAClone Run 1 IC50 (nM) Run 1 IC50 (nM)107 0.4588 6.738114 0.5069 11.89122 0.4501 7.869151 0.2759 5.671156 0.1741 4.403157 0.2902 4.647199 0.2043 5.567205 0.3487 6.690702 0.3282 -8.862705 0.3342 -8.743722 0.2851 6.298743 0.3038 6.342Example 6: Pharmacokinetic and pharmacodynamic analysis of APRIL binding proteins in non-human primates

[0274] To evaluate the impact of half-life extension mutations on APRIL-binding protein pharmacokinetics (PK), non-human primates were administered a single dose of Reference Molecule 1 (see Table 3), clone 151 having an Fc with LALA and YTE mutations, or clone 156 having an Fc with LALA and YTE mutations. Clones 151 and 156 exhibited two to three-fold increases in half-life as compared to Reference Molecule 1.

[0275] To further evaluate the PK and pharmacodynamic (PD) properties, non-human primates were intravenously administered a single dose of Antibody A or Reference Molecule 1 (see Table 3). Reference Molecule 1 was tested in its wild-type form and in a YTE-mutated form in its Fc region. Antibody A (having VH and VL sequences of SEQ ID NO: 371 and SEQ ID NO: 372, respectively) was administered at a dose of 4 mg / kg or 30 mg / kg; while Reference Molecule 1 and YTE-Reference Molecule 1 were administered at a dose of 30 mg / kg. The results confirmed the significantly longer half-life of Antibody A as compared to Reference Molecule 1. This was observed both for the wild-type form of Ref. Mol. 1 and the YTE-mutated form, which has a longer half-life than wild-type (FIGs. 4A and 4C). The half-life for Antibody A was over 3 times that of Reference Molecule 1administered at the same dose (~27 days for Antibody A vs. ~7 days for Reference Molecule 1 at a dose of 30 mg / kg) (FIG. 4A).

[0276] Furthermore, single-dose administration of Antibody A resulted in reduction in the target-mediated drug disposition (TMDD) and a deep and prolonged reduction in Immunoglobulin A (IgA), e.g., pathogenic IgA. Administration of Antibody A resulted in up to a 65% reduction in serum IgA concentration from baseline (“CFB”), which remained maximally suppressed for over 70 days or over 91 days following a single 4 mg / kg or 30 mg / kg dose, respectively (FIGs. 4B and 4D).

[0277] These results are consistent with in vitro results in a translational assay of human plasma-cell function in which peripheral B cells were isolated from human blood samples, treated with human IL-15, CpG-ODN and recombinant human APRIL, then treated with Reference Molecule 1, an isotype control, or Antibody A and assessed for IgA production by ELISA (FIG. 5A) or APRIL-induced plasma cell proliferation (FIG. 5B), both of which were completely inhibited by treatment of Antibody A.

[0278] To further evaluate the PK and PD properties of Antibody A, non-human primates were subcutaneously (SC) administered a single dose of Antibody A at 10 mg / kg or 100 mg / kg. The results for mean concentration over time are shown in FIG. 6A. The results for serum IgA concentration over time are shown in FIG. 6B. The results showed that the long- half life of Antibody A and the prolonged reduction in IgA mediated by Antibody A also were observed with subcutaneous administration of the antibody.

[0279] The results of the pharmacokinetic studies comparing Antibody A and Reference Molecule 1 are summarized below in Table 7, wherein for all parameters except Fabs, the value in parentheses is the coefficient of variation and for Fabs the value in parentheses is the 95% confidence interval (95% CI).Table 7

[0280] The results shown in Table 7 confirm that Antibody A has a half-life at least 3 times longer than Reference Molecule 1, whether administered intravenously or subcutaneously.

[0281] The results described herein demonstrate the extended half-life of Antibody A, as well as its ability to mediate deep and sustained IgA reductions and to successfully mitigate the impact of TMDD. TMDD has been a challenge for other anti-APRIL mAbs, significantly limiting the dosing interval of those agents, by requiring them to target high Ctrough values to avoid the loss of pharmacological activity that accompanies the rapid clearance associated with TMDD. Following a single 30 mg / kg IV dose in non-human primates, Reference Molecule 1 had a short linear clearance phase with a half-life of ~7-days, before demonstrating rapid non-linear clearance at concentrations below 40 ug / mL, which resulted in a loss of pharmacologic activity and corresponded to serum IgA reductions returning back toward baseline (FIGs. 4A-4D). Engineering YTE half-life extension on the IgGl framework into Reference Molecule 1 incrementally extended linear half-life by ~2-fold, but had no impact on the entry into the rapid non-linear clearance phase at the TMDD threshold of around 40 ug / mL, resulting in an only modestly extended IgA reduction (FIGs. 4C and 4D).

[0282] In contrast, a single 30 mg / kg IV dose of Antibody A in non-human primates demonstrated an extended and low linear clearance phase, with a half-life of ~27 days, nearly 4-fold longer than Reference Molecule 1, and continued linear clearance down to about 2 ug / mL, well below the Reference Molecule 1 TMDD threshold of 40 ug / mL (FIGs. 4A and 4C). The long half-life of Antibody A, along with its ability to mitigate TMDD, resulted in a deep and sustained reduction in IgA greater than 100 days following a single 30 mg / kg dose in non-human primates, before initiating IgA recovery towards baseline (FIG. 4D). Furthermore, a 7.5-fold lower dose of Antibody A at 4 mg / kg outperformed the IgAreductions of both Reference Molecule 1 and YTE-half-life extended Reference Molecule 1 dosed at 30 mg / kg (FIG. 4D).

[0283] The studies with SC administration of Antibody A in non-human primates showed high bioavailability and reproduced the long slow linear clearance phase and sustained IgA reductions observed following administration at saturating doses (FIGs. 6A and 6B). Following a single 100 mg / kg SC dose in non-human primates, the apparent linear half-life exceeds 30 days (Table 7 and FIG. 6A).Example 7: Additional studies on blocking activity of anti-huAPRIL antibodies

[0284] To further study the blocking activity of the anti-huAPRIL antibodies of the disclosure, additional studies on blocking activity were conducted using competitive ELISA experiments with BCMA and TACI as described in Example 4. The results for the additional competitive ELISA results with Antibody A are shown in FIG. 7A (BCMA) and FIG. 7B (TACI), which confirmed that Antibody A blocks binding of APRIL to both BCMA and TACI. The IC50 for inhibition of BCMA binding was 1.9 nM. The IC50 for inhibition of TACI binding was 1.03 nM.Example 8: Additional studies on functional activity of anti-huAPRIL antibodies

[0285] To further study the functional activity of the anti-huAPRIL antibodies of the disclosure, additional studies on functional activity were conducted using NFKB-LUC reporter experiments as described in Example 5. The results for the additional NFKB-LUC reporter assay with Antibody A are shown in FIG. 7C (BCMA) and FIG. 7D (TACI), which confirmed that Antibody A inhibits APRIL-mediated signaling. The IC50 for inhibition of APRIL / BCMA-mediated signaling was 5.97 nM. The IC50 for inhibition of APRIL / TACI- mediated signaling was 0.22 nM.Example 9: Anti-huAPRIL Antibody Avoids High Molecular Weight Complex Formation

[0286] High molecular weight (MW) complex formation between an antibody and its target can lead to tissue damage. The process for a trimeric protein such as APRIL isillustrated schematically in FIG. 8. The process is initiated by antibody binding to trimeric APRIL leading to high MW complex formation through a "daisy-chain"-like phenomenon. This can lead to rapid clearance of the antibody from the plasma and TMDD, as well as the development of anti-drug antibodies (ADA) and the generation of tissue damage mediated by tissue accumulation of the complexes and / or complement activation. The anti-APRIL antibodies of the disclosure, such as Antibody A discussed below, avoid high MW complex formation, thereby potentially mitigating the risks of immunogenicity and TMDD.

[0287] High MW complex formation by Antibody A and Reference Molecule 1 in the presence and absence of APRIL was evaluated by SEC-MALS. Human APRIL and anti- APRIL antibody were mixed at 1 :5 ratio (12 and 60 pM, respectively) in PBS pH 7.4 and incubated for 48 h at 37 °C. Twenty pg of each sample were analyzed by SEC-HPLC using a Waters XBridge Premier Protein SEC column (250A, 2.5 pm, 4.6 x 300 mm) with a MaxPeak Premier Protein SEC pre-column (250A, 2.5 pm, 4.6 x 30 mm) in a Vanquish™ Flex UHPLC System. The dRI (differential refractive index) and MALS (multi-angle light scattering) analysis were performed using Wyatt Optilab and DAWN8 instruments.

[0288] The results for APRIL alone are shown in FIG. 9. The results for Reference Molecule 1 are shown in FIG. 10. The results for Antibody A are shown in FIG. 11. A comparison of the results for APRIL alone, Reference Molecule 1 + APRIL and Antibody A + APRIL is shown in FIG. 12. The results demonstrate that Antibody A exhibits reduced high MW complex formation compared to Reference Molecule 1.Example 10: A Translational Framework for Development of Antibody A

[0289] IgA nephropathy (IgAN) is an autoimmune kidney disease characterized by mesangial deposition of immune complexes containing IgA and Gd-IgAl. Blocking A proliferation-inducing ligand (APRIL) is potentially disease modifying in IgAN by reducing IgA, Gd-IgAl and proteinuria, ultimately stabilizing kidney function. Antibody A is a novel APRIL neutralizing monoclonal antibody (mAb) designed for high affinity and extended half-life. Biomarker responses to APRIL inhibition were leveraged to assess preclinical to clinical translation and the consistency of pharmacokinetic (PK) and pharmacodynamic (PD) responses in healthy volunteers (HV) and IgAN patients to support development of APRIL targeted therapies in IgAN.

[0290] Methods

[0291] Translational PKPD models and statistical correlation were used to integrate preclinical data from the Antibody A development program with publicly available clinical data from anti-APRIL mAbs and other IgA-depleting agents (dual APRIL / BAFF inhibitors and anti-CD38 mAbs). Correlation coefficients (r) were used to estimate correlations between key pharmacologic properties and PKPD endpoints relevant to IgAN drug development.

[0292] Results

[0293] In vitro APRIL binding affinity is predictive of in vivo IgA reduction in nonhuman primates (r=0.99) and humans (r=0.99). The kinetics of a panel of anti-APRIL antibodies were evaluated, with PK and APRIL neutralization profiles compared over time in healthy volunteers and patients with IgAN. The results demonstrated no discernible kinetic differences and a direct relationship between anti-APRIL antibody concentration and target neutralization. Moreover, clinical data reveal consistent anti-APRIL mAb PK with a direct relationship between PK and APRIL neutralization leading to predictable IgA reduction in healthy volunteers (HVs) and IgAN patients with a strong association (r=0.93) across mechanisms. IgA and Gd-lgAl reductions are correlated in IgAN patients (r=0.96). IgA reduction at 8 weeks of treatment in IgAN patients is correlated with proteinuria reduction after 36 weeks of treatment (r=0.89). The magnitude of APRIL neutralization and proteinuria reduction were correlated in IgAN patients (r=0.96). The magnitude of APRIL neutralization also was correlated with partial remission in IgAN patients (r=0.84).

[0294] Conclusions

[0295] Tightly correlated biomarker responses to APRIL blockade enable preclinical and HV clinical data to potentially predict clinical responses in IgAN patients. The depth and duration of APRIL inhibition is anticipated to predict clinical activity, reflect diseasemodifying potential, and define dose and dose interval for IgAN patient trials. The PK, APRIL and IgA HV data can be used to define the dose and schedule designed to fully suppress APRIL throughout the dosing interval in IgAN patients. Complete APRIL neutralization in HVs appears to ultimately predict deep IgA and Gd-lgAl suppression and maximal proteinuria reductions in IgAN patients. These associations provide a foundation for Antibody A development, a potentially disease modifying therapy in IgAN with convenient, infrequent dosing.Example 11: Nonclinical Safety Profile of Antibody A

[0296] IgA nephropathy (IgAN) is a chronic autoimmune kidney disease characterized by mesangial deposition of immune complexes containing IgA and Gd-IgAl. A proliferationinducing ligand (APRIL) is critical in driving production of Gd-IgAl through IgA class switching. Blocking APRIL reduces Gd-IgAl levels resulting in reduced proteinuria and preservation of kidney function in IgAN patients. Evaluation of anti-APRIL therapies has consistently shown a favorable safety profile in healthy volunteers and IgAN patients. Antibody A is a fully human anti-APRIL monoclonal antibody (mAb) engineered for high affinity, to limit effector function and to extend half-life. Studies were conducted to characterize the nonclinical safety profile of Antibody A.

[0297] Methods

[0298] Nonclinical safety studies conducted with Antibody A included an in vitro membrane protein array, a human tissue cross-reactivity assay, an in vitro cytokine release assay with human whole blood, and repeat-dose studies in non-human primates (NHP). In vivo studies included evaluation of immunoglobulins (Ig), cytokines, B cell activating factor (BAFF), immunophenotyping, T cell-dependent antibody response (TDAR) and histology.

[0299] Results

[0300] To test for off-target binding, human membrane proteins (>6000) were expressed in individual wells of HEK-293T cells arrayed in 384 well plates and Antibody A binding was assessed by flow cytometry. The results showed that there was no off-target binding of Antibody A to the panel of human membrane proteins. Specific binding of biotinylated Antibody A was assessed by immunohistochemistry in a panel of 37 frozen tissues, the results of which showed that Antibody A showed no cell membrane binding in the panel of 37 human tissues. To determine whether any histological changes occurred in vivo, NHPs were dosed with Antibody A subcutaneously (SC) at 0, 40, 80 or 174 mg / kg / dose Q2W (days 1, 15, 29) and tissues were collected at the end of the dosing phase for histological evaluation. The results demonstrated that Antibody A showed no histological changes in NHP tissues.

[0301] Fc receptor and Clq binding studies confirmed that Antibody A has minimal effector function.

[0302] To assess cytokine release in vitro, PBS-treated whole blood samples were incubated with increasing concentrations of Antibody A (0.1 ug / ml - 100 ug / ml) and release of cytokines (IL- 10, IL-2, IL-4, IL-6, TNF-a and IFN-y) was measured after 24 hours of incubation. The results showed that Antibody A was not associated with cytokine release in human whole blood in vitro. To assess in vivo release of cytokines, NHPs were dosed SC with Antibody A at 0, 40, 80 or 174 mg / kg / dose Q2W (days 1, 15, 29), serum samples were collected after the dosing phase and analyzed for cytokine levels (IL- lb, IL-6, IL-8, MCP-1, and TNF-a). The results demonstrated that Antibody A administration in NHPs does not elicit cytokine release.

[0303] To assess the effect of Antibody A on BAFF levels in vivo. NHPs were dosed with Antibody A intravenously (IV) at 10 mg / kg single dose or SC at 75 or 150 mg / kg Q2W (Days 1, 15, 29), serum samples were collected after the dosing phase and analyzed for BAFF levels. The results demonstrated that Antibody A administration in NHPs does not induce BAFF.

[0304] Antibody A was well tolerated in NHP studies up to the highest dose tested providing wide safety margins above the anticipated therapeutic dose.

[0305] To assess the effect of Antibody A on immunoglobulin levels in vivo, NHPs were dosed with a single dose of Antibody A IV at 4 or 30 mg / kg or SC at 10 or 100 mg / kg. Serum samples were collected and analyzed for immunoglobulin levels (IgA, IgM and IgG). NHPs at 10 and 100 mg / kg SC were sampled out to 115 days post-dose, NHPs at 4 mg / kg IV were sampled out to 123 days post-dose, and NHPs at 30 mg / kg IV were sampled out to 210 days post-dose. IgA and IgM reductions ranged from 54.7-67.6% (IgA) and 61.5-75.4% (IgM) from baseline. IgG reductions ranged from 34.6-47.7% from baseline. IgA, IgM, and IgG levels returned predictably towards baseline following Antibody A clearance. Thus, Antibody A administration in NHPs resulted in reductions in immunoglobulins consistent with an IgG- sparing mechanism of action.

[0306] To assess the effect of Antibody A on immune cell populations, NHPs were dosed with Antibody A SC at 0, 40. 80 or 174 mg / kg / dose Q2W (Days 1, 15, 29). Immune cells (CD4+ T cells, CD8+ T cells, B cells and NK cells) were characterized by flow cytometry pre-study and on Days 4, 15, 18. 32, and 99 (control and high dose only). The results showed that Antibody A administration did not impact immune ceil populations

[0307] To assess the effect of Antibody A on antigenic responses in vivo, NHPs were dosed with Antibody A SC at 0, 40, 80 and 174 mg / kg / dose Q2W for 26 weeks. The antigen keyhole limpet hemocyanin (KLH) was administered on Days 127 and 155. Anti-KLH IgG and IgM antibodies were quantitated using an ELISA assay at several timepoints following KLH administration. The results showed robust responses to KLH, with kinetics comparable to control, thereby demonstrating lack of immunosuppression in Antibody A-treated NHPs.

[0308] Conclusions

[0309] Nonclinical studies demonstrate that Antibody A binds APRIL with high specificity and has low potential for off-target binding to human proteins, low potential to induce cytokine release and no specific cell membrane binding in human tissues. Consistent with the mechanism of action, Antibody A resulted in marked reductions of IgA and IgM, and modest reductions in IgG in NHPs (IgG sparing), all of which returned towards baseline following Antibody A clearance. Despite reductions in immunoglobulins, Antibody A-treated NHPs mounted robust humoral responses to KLH antigen with kinetics comparable to control (consistent with responses to tetanus / diptheria in healthy volunteers). Additionally, Antibody A was well tolerated in NHPs at high dose levels, with no histological effects or effects on immune cells, soluble BAFF levels or cytokines, providing wide safety margins above the anticipated human doses. By potently blocking APRIL-mediated signaling, Antibody A has the potential to provide disease-modifying treatment to IgAN patients with low risk of toxicity and no impact on circulating immune cells.OTHER EMBODIMENTS

[0310] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features set forth herein.

Claims

1. WHAT IS CLAIMED IS:

1. An APRIL-binding protein comprising a heavy chain variable domain (VH) that is at least 95% identical to that of SEQ ID NO: 263, wherein the VH comprises a heavy chain complementarity -determining region, CDR-H3, comprising the amino acid sequence of SEQ ID NO: 267, 272, or 276.

2. The APRIL-binding protein of claim 1, wherein:(i) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 267 and the VH further comprises complementarity-determining regions:CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 266;(ii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 272 and the VH further comprises complementarity-determining regions:CDR-H1 comprising the amino acid sequence of SEQ ID NO: 270; andCDR-H2 comprising the amino acid sequence of SEQ ID NO: 271; or(iii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 276 and the VH further comprises complementarity-determining regions:CDR-H1 comprising the amino acid sequence of SEQ ID NO: 274; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 275.

3. The APRIL-binding protein of claim 1 or 2, further comprising a light chain variable domain (VL) comprising complementarity-determining regions:(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 268;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 269;(b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 273;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 269; or(c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 277;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 278.

4. The APRIL-binding protein of any one of claims 1-3, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 264.

5. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 266; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 267; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 268;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 269;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 270;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 271; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 272; and(ii) a light chain variable domain (V ) comprising complementarity -determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 273;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 269; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 274;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 275; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 276; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 277;CDR-L2 comprising the amino acid sequence A AS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 278.

6. An APRIL-binding protein comprising a heavy chain variable domain (VH) that is at least 95% identical to that of SEQ ID NO: 279, wherein the VH comprises a heavy chain complementarity -determining region, CDR-H3, comprising the amino acid sequence of SEQ ID NO: 267, 272, or 276.

7. The APRIL-binding protein of claim 6, wherein:(i) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 267 and the VH further comprises complementarity-determining regions:CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 281;(ii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 272 and the VH further comprises complementarity-determining regions:CDR-H1 comprising the amino acid sequence of SEQ ID NO: 284; andCDR-H2 comprising the amino acid sequence of SEQ ID NO: 285; or(iii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 276 and the VH further comprises complementarity-determining regions:CDR-H1 comprising the amino acid sequence of SEQ ID NO: 287; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 288.

8. The APRIL-binding protein of claim 6 or 7, further comprising a light chain variable domain (VL) comprising complementarity-determining regions:(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 282;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 283;(b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 286;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 283; or(c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 289;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 290.

9. The APRIL-binding protein of any one of claims 6-8, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 280.

10. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 281; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 267; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 282;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 283;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 284;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 285; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 272; and(ii) a light chain variable domain (VL) comprising complementarity -determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 286;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 283; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 287;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 288; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 276; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 289;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 290.

11. An APRIL-binding protein comprising a heavy chain variable domain (VH) that is at least 95% identical to that of SEQ ID NO: 291, wherein the VH comprises a heavy chain complementarity-determining region, CDR-H3, comprising the amino acid sequence of SEQ ID NO: 294, 297, or 300.

12. The APRIL-binding protein of claim 11, wherein:(i) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 294 and the VH further comprises complementarity-determining regions:CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265; andCDR-H2 comprising the amino acid sequence of SEQ ID NO: 293;(ii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 297 and the VH further comprises complementarity-determining regions:CDR-H1 comprising the amino acid sequence of SEQ ID NO: 284; andCDR-H2 comprising the amino acid sequence of SEQ ID NO: 296; or(iii) the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 300 and the VH further comprises complementarity-determining regions:CDR-H1 comprising the amino acid sequence of SEQ ID NO: 287; and CDR-H2 comprising the amino acid sequence of SEQ ID NO: 299.

13. The APRIL-binding protein of claim 11 or 12, further comprising a light chain variable domain (VL) comprising complementarity-determining regions:(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 268;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 295;(b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 273;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 295; or(c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 277;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 301.

14. The APRIL-binding protein of any one of claims 11-13, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 292.

15. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 293; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 294; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 268;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 295;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 284;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 296; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 297; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 273;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 295;or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 287;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 299; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 300; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 277;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 301.

16. An APRIL-binding protein comprising a heavy chain variable domain (VH) comprising complementarity -determining regions:(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 305; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 306;(b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 311; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 312; or(c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 314; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 315.

17. The APRIL-binding protein of claim 16, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 302.

18. The APRIL-binding protein of claim 16 or 17, further comprising a light chain variable domain (VL) comprising complementarity-determining regions:(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 307;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 309;(b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 313;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 309; or(c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 316;CDR-L2 comprising the amino acid sequence LGS ; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 317.

19. The APRIL-binding protein of any one of claims 16-18, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 303.

20. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 305; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 306; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 307;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 309;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 311; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 312; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 313;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 309; or(c)(i) a heavy chain variable domain (Vn) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 314; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 315; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 316;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 317.

21. An APRIL-binding protein comprising:(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322;and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 323;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 324;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 328;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 324; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:180CDR-L1 comprising the amino acid sequence of SEQ ID NO: 332;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.

22. The APRIL-binding protein of claim 21, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 318.

23. The APRIL-binding protein of claim 21 or 22, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 319.

24. An APRIL-binding protein comprising:(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 323;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and181(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 328;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 332;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.

25. The APRIL-binding protein of claim 24, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 334.

26. The APRIL-binding protein of claim 24 or 25, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 335.

27. An APRIL-binding protein comprising a heavy chain variable domain (VH) comprising complementarity -determining regions:(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 339; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322;(b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 341; and182CDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; or(c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 343; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331.

28. The APRIL-binding protein of claim 27, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 337.

29. The APRIL-binding protein of claim 27 or 28, further comprising a light chain variable domain (VL) comprising complementarity-determining regions:(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 340;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 336;(b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 342;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or(c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 344;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.

30. The APRIL-binding protein of any one of claims 27-29, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 338.

31. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 339; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:183CDR-L1 comprising the amino acid sequence of SEQ ID NO: 340;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 341; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 342;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 343; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 344;CDR-L2 comprising the amino acid sequence LGS; and184CDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.

32. An APRIL-binding protein comprising a heavy chain variable domain (VH) comprising complementarity-determining regions:(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 347; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322;(b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 350; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 351 ; or(c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 354; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331.

33. The APRIL-binding protein of claim 32, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 345.

34. The APRIL-binding protein of claim 32 or 33, further comprising a light chain variable domain (VL) comprising complementarity-determining regions:(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 348;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 349;(b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 352;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; or(c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 355;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 356.

35. The APRIL-binding protein of any one of claims 32-34, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 346.

36. An APRIL-binding protein comprising(a)185(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 347; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 348;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 349;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 350; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 351; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 352;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32;186CDR-H2 comprising the amino acid sequence of SEQ ID NO: 354; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 355;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 356.

37. An APRIL-binding protein comprising a heavy chain variable domain (VH) comprising complementarity -determining regions:(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 359; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322;(b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 361; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 351; or(c) CDR-H 1 comprising the amino acid sequence of SEQ ID NO: 32;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 363; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331.

38. The APRIL-binding protein of claim 37, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 357.

39. The APRIL-binding protein of claim 37 or 38, further comprising a light chain variable domain (VL) comprising complementarity-determining regions:(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 360;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 349;(b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 362;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; or(c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 364;CDR-L2 comprising the amino acid sequence LGS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 356.

40. The APRIL-binding protein of any one of claims 37-39, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 358.

41. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 359; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 360;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 349;(b)(i) a heavy chain variable domain (VII) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 361; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 351; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 362;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 363; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 364;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 356.

42. An APRIL-binding protein comprising:(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining189CDR-L1 comprising the amino acid sequence of SEQ ID NO: 367;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 368;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 369;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 368; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 370;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 317.19043. The APRIL-binding protein of claim 42, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 365.

44. The APRIL-binding protein of claim 42 or 43, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 366.

45. An APRIL-binding protein comprising:(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 373;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 309;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 373;CDR-L2 comprising the amino acid sequence LGS; and191CDR-L3 comprising the amino acid sequence of SEQ ID NO: 309; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 374;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 317.

46. The APRIL-binding protein of claim 45, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 371.

47. The APRIL-binding protein of claim 45 or 46, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 372.

48. An APRIL-binding protein comprising a heavy chain variable domain (VH) comprising complementarity-determining regions:(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 347; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 377;(b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 379;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 350; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 380; or(c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 382;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 354; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 383.19249. The APRIL-binding protein of claim 48, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 375.

50. The APRIL-binding protein of claim 48 or 49, further comprising a hght chain variable domain (VL) comprising complementarity-determining regions:(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 378;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336;(b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 381;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or(c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 384;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.51 . The APRIL-binding protein of any one of claims 48-50, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 376.

52. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 347; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 377; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 378;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336;193(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 379;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 350; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 380; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 381;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 382;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 354; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 383; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 384;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 333.

53. An APRIL-binding protein comprising(a)194(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 387;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 388; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 389; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 390;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 391;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 392;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 393; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 394; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 395;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 391 ; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 396;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 397; and195CDR-H3 comprising the amino acid sequence of SEQ ID NO: 398; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 399;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 400.

54. The APRIL-binding protein of claim 53, wherein the VH comprises the amino acid sequence of SEQ ID NO: 385.

55. The APRIL-binding protein of claim 53 or 54, wherein the VL comprises the amino acid sequence of SEQ ID NO: 386.

56. The APRIL-binding protein of any one of claims 1-55, wherein the APRIL-binding protein is an antibody or antigen-binding fragment thereof.

57. The APRIL-binding protein of claim 56, wherein the APRIL-binding protein is a human antibody or antigen-binding fragment thereof.

58. The APRIL-binding protein of claim 56 or 57, wherein antigen-binding fragment is a Fab, a F(ab’)2, a Fab’, a single-chain Fv (scFv), an Fv fragment, a Fd fragment, or a diabody.

59. The APRIL-binding protein of any one of claims 56-58, wherein the antibody or antigen-binding fragment thereof comprises an Fc region.

60. The APRIL-binding protein of claim 59, wherein the Fc region is an IgGl, IgG2, or IgG4 Fc region.

61. The APRIL-binding protein of claim 59, wherein the Fc region is an IgGl Fc region.

62. The APRIL-binding protein of claim 60 or 61, wherein the Fc region is a modified Fc region.

63. The APRIL-binding protein of claim 62, wherein the modified Fc region comprises the specific combination of amino acid substitutions of LALA / YTE.19664. The APRIL-binding protein of claim 62 or 63, wherein the modified Fc region comprises a half-life extending mutation or set of half-life extending mutations.

65. The APRIL-binding protein of claim 64, wherein the set of half-life extending mutations is selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

66. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 416, and the light chain comprises the amino acid sequence of SEQ ID NO: 417.

67. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 418, and the light chain comprises the amino acid sequence of SEQ ID NO: 419.

68. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 420, and the light chain comprises the amino acid sequence of SEQ ID NO: 421.

69. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 422, and the light chain comprises the amino acid sequence of SEQ ID NO: 423.

70. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 424, and the light chain comprises the amino acid sequence of SEQ ID NO: 425.

71. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 426, and the light chain comprises the amino acid sequence of SEQ ID NO: 427.

72. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 428, and the light chain comprises the amino acid sequence of SEQ ID NO: 429.19773. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 430, and the light chain comprises the amino acid sequence of SEQ ID NO: 431.

74. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 432, and the light chain comprises the amino acid sequence of SEQ ID NO: 433.

75. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 434, and the light chain comprises the amino acid sequence of SEQ ID NO: 435.

76. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 436, and the light chain comprises the amino acid sequence of SEQ ID NO: 437.

77. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 438, and the light chain comprises the amino acid sequence of SEQ ID NO: 439.

78. An APRIL-binding protein comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 440, and the light chain comprises the amino acid sequence of SEQ ID NO: 441.

79. An APRIL-binding protein comprising a heavy chain variable domain (VH) that is at least 95% identical to that of SEQ ID NO: 263, wherein the VH comprises a heavy chain complementarity -determining region, CDR-H3, comprising the amino acid sequence of SEQ ID NO: 267, 272, or 276, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

80. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 266; and198CDR-H3 comprising the amino acid sequence of SEQ ID NO: 267; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 268;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 269;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 270;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 271 ; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 272; and(ii) a light chain variable domain (VL) comprising complementarity -determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 273;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 269; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 274;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 275; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 276; and199(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 277;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 278, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

81. An APRIL-binding protein comprising a heavy chain variable domain (VH) that is at least 95% identical to that of SEQ ID NO: 279, wherein the VH comprises a heavy chain complementarity -determining region, CDR-H3, comprising the amino acid sequence of SEQ ID NO: 267, 272, or 276.

82. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 281 ; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 267; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 282;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 283;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 284;200CDR-H2 comprising the amino acid sequence of SEQ ID NO: 285; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 272; and(ii) a light chain variable domain (VL) comprising complementarity -determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 286;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 283; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 287;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 288; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 276; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 289;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 290, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

83. An APRIL-binding protein comprising(a)201(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 265;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 293; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 294; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 268;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 295;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 284;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 296; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 297; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 273;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 295; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 287;202CDR-H2 comprising the amino acid sequence of SEQ ID NO: 299; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 300; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 277;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 301, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

84. An APRIL-binding protein comprising a heavy chain variable domain (VH) comprising complementarity -determining regions:(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 305; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 306;(b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 311; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 312; or(c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 314; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 315, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

85. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 305; and203CDR-H3 comprising the amino acid sequence of SEQ ID NO: 306; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 307;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 309;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 311 ; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 312; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 313;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 309; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 314; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 315; and204(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 316;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 317, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

86. An APRIL-binding protein comprising:(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 323;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 324;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and205(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 328;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 324; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 332;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 333, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

87. An APRIL-binding protein comprising:(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and206(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 323;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 328;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 332;207CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 333, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

88. An APRIL-binding protein comprising a heavy chain variable domain (VH) comprising complementarity -determining regions:(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 339; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322;(b) CDR-H 1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 341; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; or(c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 343; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

89. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 339; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 340;208CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 341; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 342;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 343; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 344;CDR-L2 comprising the amino acid sequence LGS; and209CDR-L3 comprising the amino acid sequence of SEQ ID NO: 333, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

90. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 347; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 348;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 349;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 350; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 351; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 352;CDR-L2 comprising the amino acid sequence LGS; and210CDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 354; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 355;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 356, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

91. An APRIL-binding protein comprising a heavy chain variable domain (VH) comprising complementarity -determining regions:(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 359; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322;(b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 361; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 351; or(c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 363; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.21192. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 359; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 360;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 349;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 310;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 361; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 351; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 362;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 349; or(c)212(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 363; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 364;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 356, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

93. An APRIL-binding protein comprising:(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 367;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 368;(b)213(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 369;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 368; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 370;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 317, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

94. An APRIL-binding protein comprising:(a)214(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 322; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 373;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 309;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 325;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 326; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 327; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 373;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 309; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 329;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 330; and215CDR-H3 comprising the amino acid sequence of SEQ ID NO: 331; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 374;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 317, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

95. An APRIL-binding protein comprising a heavy chain variable domain (VH) comprising complementarity -determining regions:(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 347; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 377;(b) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 379;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 350; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 380; or(c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 382;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 354; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 383, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

96. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320;216CDR-H2 comprising the amino acid sequence of SEQ ID NO: 347; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 377; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 378;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 379;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 350; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 380; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 381;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 336; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 382;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 354; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 383;217and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 384;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 333, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

97. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 387;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 388; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 389; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 390;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 391;(b)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 392;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 393; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 394;218and(ii) a light chain variable domain (VL) comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 395;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 391 ; or(c)(i) a heavy chain variable domain (VH) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 396;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 397; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 398; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 399;CDR-L2 comprising the amino acid sequence LGS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 400, and an Fc region comprising a means for enhancing the half-life of the APRIL-binding protein.

98. An isolated nucleic acid encoding the APRIL-binding protein of any one of claims 1-97.

99. An expression vector comprising the isolated nucleic acid of claim 98.

100. A host cell comprising the isolated nucleic acid molecule of claim 98 or the expression vector of claim 99.

101. A method of preparing an APRIL-binding protein comprising culturing the host cell of claim 100 such that an APRIL-binding protein is expressed by the host cell.219102. The method of claim 101, wherein the APRIL-binding protein is isolated from the host cell or culture supernatant.

103. A pharmaceutical composition comprising the APRIL-binding protein of any one of claims 1 -97 and a pharmaceutically acceptable carrier.

104. A method comprising a step of administering to a subject in need thereof an effective amount of the APRIL-binding protein of any one of claims 1-97 or the pharmaceutical composition of claim 103.

105. The method of claim 104, wherein the subject has an autoimmune or inflammatory disease or disorder.

106. The method of claim 105, wherein the subject has a disease or disorder selected from the group consisting of IgA nephropathy, myasthenia gravis, systemic lupus erythematosus, membranous glomerulonephritis, Sjbgrens disease, lupus nephritis, immune thrombocytopenia, acquired (autoimmune) hemolytic anemia, cold agglutinin disease (CAD), autoimmune hepatitis, multiple sclerosis, pemphigus vulgaris, and rheumatoid arthritis, hidradenitis suppurativa, ANCA-associated vasculitis (AAV), IgA Vasculitis, Minimal Change Disease (MCD), Focal Segmental Glomerulosclerosis (FSGS), Primary Nephrotic Syndrome, Systemic Sclerosis, Antineutrophil Cytoplasmic Antibody-associated Vasculitis, Nephritis, anti-NMDAR and anti-LGIl encephalitis, Connective tissue disease-associated thrombocytopenia, and Celiac Disease.

107. The method of claim 105, wherein the subject has IgA nephropathy.

108. The method of claim 104, wherein the subject has an IgM-mediated disease.

109. The method of claim 108, wherein the IgM-mediated disease is selected from the group consisting of multifocal motor neuropathy (“MMN”), anti-MAG (myelin-associated glycoprotein) neuropathy, and cold agglutinin disease (“CAD”).

110. The method of claim 104, wherein the subject has an allergic disease or disorder.

111. The method of claim 110, wherein the allergic disease or disorder is selected from the group consisting of food allergies, respiratory allergies, chemical allergies, asthma, hives, atopic dermatitis (eczema) or contact dermatitis.

112. The method of any one of claims 104-111, wherein the step of administering220comprises systemic administration of the APRIL-binding protein.

113. The method of claim 112, wherein the systemic administration comprises intravenous or subcutaneous administration.

114. The method of any one of claims 104-113, which further comprising administering at least one additional therapeutic agent to the subject.221