April binding proteins, compositions, and methods of use thereof

Abstract

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

Description

JDJ-073PC PRG-073WOAPRIL BINDING PROTEINS, COMPOSITIONS, AND METHODS OF USETHEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 687,707 (filed August 27, 2024), U.S. Provisional Application No. 63 / 687,715 (filed August 27, 2024), U.S. Provisional Application No. 63 / 687,720 (filed August 27, 2024), U.S. Provisional Application No. 63 / 687,760 (filed August 27, 2024), U.S. Provisional Application No. 63 / 687,562 (filed August 27, 2024), U.S. Provisional Application No.63 / 687,687 (filed August 27, 2024), U.S. Provisional Application No. 63 / 687,690 (filed August 27, 2024), U.S. Provisional Application No. 63 / 687,692 (filed August 27, 2024), and U.S. Provisional Application No. 63 / 687,765 (filed August 27, 2024), the entire disclosure of which is hereby incorporated by reference in its entirety for all purposes.SEQUENCE LISTING

[0002] 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 August 26, 2025 is named JDJ-073PC_SL.xml and is 260 KB in size.BACKGROUND

[0003] The B cell-activating factor / a proliferation-inducing ligand (BAFF / 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 and have shown considerable variability in their efficacy.

[0004] There remains a need for improved therapeutics targeting APRIL.JDJ-073PCPRG-073WOSUMMARY

[0005] The present invention addresses this need with APRIL binding proteins, as well as related compositions and methods. In some embodiments, provided binding proteins and compositions exhibit improved therapeutic efficacy and / or half-lives relative to existing APRIL-targeting therapeutics.

[0006] 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.

[0007] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 1.

[0008] 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.

[0009] 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-JDJ-073PCPRG-073WOL2 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 (Vn) 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 (Vn) 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.

[0010] 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.

[0011] In some embodiments, the Vn comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 19.

[0012] 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;JDJ-073PCPRG-073WOCDR-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.

[0013] In some embodiments, provided are APRIL-binding proteins comprising (a) (i) a heavy chain variable domain (Vn) 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 SEQ ID 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 (VH) 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.

[0014] 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.JDJ-073PCPRG-073WO

[0015] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 37.

[0016] 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 ID NO: 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.

[0017] In some embodiments, the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 38.

[0018] 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-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; and (ii) a light chain variable domain (VL) comprising complementaritydetermining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 53; CDR-JDJ-073PCPRG-073WOL2 comprising the amino acid sequence WAS; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 54.

[0019] 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: 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; (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.

[0020] In some embodiments, the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 55.

[0021] 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.

[0022] 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 acidJDJ-073PCPRG-073WO 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 (Vi.) 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.

[0023] 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.

[0024] 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.JDJ-073PCPRG-073WO

[0025] 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: 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.

[0026] 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.JDJ-073PCPRG-073WO

[0027] 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 sequence of SEQ ID NO: 103; or (c) CDR-LI 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.

[0028] 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-LI 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-LI 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-LI 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.

[0029] In one aspect, provided are APRIL-binding proteins comprising a heavy chain variable domain (VH) comprising complementarity-determining regions: (a) CDR-H1JDJ-073PCPRG-073WO 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; (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 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. In some embodiments, the Vn comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 109.

[0030] 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: 1 16; (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.

[0031] 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: 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 ;JDJ-073PCPRG-073WO 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) comprising complementarity -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.

[0032] 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.

[0033] 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.

[0034] 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 complementarity-JDJ-073PCPRG-073WO determining 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.

[0035] In some embodiments, the APRIL binding protein is an antibody or antigenbinding fragment thereof, e.g., a human antibody or antigen-binding fragment thereof.

[0036] 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.

[0037] In some embodiments, the antibody or antigen binding fragment thereof comprises an Fc region, e.g., an IgGl, IgG2, or IgG4 Fc region.

[0038] 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 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 / Q311H / N434S (DHS).

[0039] In one aspect, provided are isolated nucleic acids encoding an APRIL-binding protein as disclosed herein.

[0040] In one aspect, provided are expression vectors comprising isolated nucleic acids as disclosed herein.JDJ-073PCPRG-073WO

[0041] In one aspect, provided are host cells comprising isolated nucleic acid molecules or expression vectors as disclosed herein.

[0042] In one aspect, provided are pharmaceutical compositions comprising an APRIL- binding protein as disclosed herein and a pharmaceutically acceptable carrier.

[0043] 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, myasthenia gravis, systemic lupus erythematosus, membranous glomerulonephritis, Sjogren syndrome, lupus nephritis, immune thrombocytopenia, acquired (autoimmune) hemolytic anemia, cold agglutinin disease, autoimmune hepatitis, multiple sclerosis, pemphigus vulgaris, and rheumatoid arthritis.

[0044] In some embodiments, the step of administering comprises systemic administration of the APRIL-binding protein, for example, systemic administration comprising intravenous or subcutaneous administration.BRIEF DESCRIPTION OF THE DRAWINGS

[0045] FIGs. 1A and IB show binding curves from surface plasmon resonance (SPR) experiments, for anti-APRIL antibodies against human APRIL (FIG. 1A) or cynomolgus APRIL (FIG. IB).

[0046] FIGs. 2A and 2B 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 (FIG. 2A) or to BCMA (FIG. 2B). 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 I, 2, 3, and / or 4 (which have the sequences as shown in Table 3) are shown for comparison.

[0047] FIGs. 3A and 3B show results from NFKB luciferase reporter experiments to assess the ability of anti-APRIL antibodies to block interaction between human APRIL and human TACI (FIG. 3A) or human BCMA (FIG. 3B). 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.JDJ-073PCPRG-073WODETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0048] In various embodiments, provided are APRIL binding proteins, compositions thereof, and methods of use thereof.Definitions

[0049] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0050] 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.

[0051] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0052] 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.

[0053] 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 calledJDJ-073PCPRG-073WO 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) I. 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.

[0054] “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 the target 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 theJDJ-073PCPRG-073WO 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).

[0055] 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 (Vn), and the first constant domain of one heavy chain (CHI). 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.

[0056] 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.

[0057] 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.

[0058] 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 regionsJDJ-073PCPRG-073WO 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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 a desired 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 theJDJ-073PCPRG-073WO binding protein or pharmaceutical composition thereof are outweighed by therapeutically beneficial effects.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.JDJ-073PCPRG-073WOImmunol. 25(1):7 (1988)); solid phase direct biotin-avidin EIA (Cheung et al., Virology 176:546 (1990)); and direct labeled RIA. (Moldenhauer et al., 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.

[0067] 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.

[0068] 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 of an immunoglobulin heavy chain, capable of stable association with another similar polypeptide. For example, an Fc chain of a dimeric IgG Fc comprises an IgG Cu2 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, e, y, and p, respectively. Several of these may be further divided into subclasses (isotypes), e.g., IgGl, lgG2, IgG3, lgG4, IgAl, and lgA2.

[0069] 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 (anJDJ-073PCPRG-073WO“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)).

[0070] 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 hypervariable region residues from a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having a desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding 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.JDJ-073PCPRG-073WO

[0071] As used herein, the term “large antigen-binding complex” refers to a 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 least 13, at least 14, at least 15, or at least 16 times that of the molecular weight of a monomer of the binding protein.

[0072] 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.

[0073] “Percent (%) identity” refers to the extent to which two sequences (nucleotide or amino acid) have the same residue at the same positions in an 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), FASTA (Pearson and Lipman, 1988; Pearson, 1990) and gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984).

[0074] 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.

[0075] 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).

[0076] 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 isJDJ-073PCPRG-073WO attached 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.

[0077] 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.

[0078] 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.

[0079] 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, 10"7M, 10"8M, 10'9M, IO10M, 10"11M, or 1012M, or less. 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-human primate species). In some embodiments, a binding protein may bind exclusively to a given target, e.g., exclusively to APRIL but not to other molecules.JDJ-073PCPRG-073WO

[0080] 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.

[0081] 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 (z.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.

[0082] 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.

[0083] 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 recitedJDJ-073PCPRG-073WO components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0084] 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

[0085] 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.

[0086] 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.

[0087] 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 (VL and CLI domains), the variable region domain of the heavy chain (VH), and the first constant domain of one heavy chain (CHI).

[0088] In some embodiments, provided APRIL-binding proteins comprise a heavy chain variable domain comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in a table selected from any of Tables 1A-1H. 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 1A-1H.

[0089] 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-1H. In some embodiments, provided APRIL-binding proteins comprise a heavyJDJ-073PCPRG-073WO chain variable domain which is a variant of the heavy chain variable sequence shown in a table selected from any of Tables 1A-1H, 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-1H 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 1A-1H.

[0090] 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-1H 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.JDJ-073PCPRG-073WOTable 1A. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOTable IB. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOTable 1C. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOTable ID. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOTable IE. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOTable IF. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOTable 1G. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOTable 1H. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of APRIL-binding proteinsJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOFc polypeptides

[0091] Binding proteins suitable for use in accordance with the present disclosure typically comprise an immunoglobulin Fc region. Fc regions typically comprises 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.

[0092] 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 K0, KI and K2 molecules (Dick et al. (2008) Biotech. Bioeng. 100:1132).

[0093] 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).

[0094] 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 2), 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 Table 2) 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).

[0095] 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 lysineJDJ-073PCPRG-073WO 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.

[0096] 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.

[0097] 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 human IgG2 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.

[0098] 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.JDJ-073PCPRG-073WOFc mutations

[0099] In certain embodiments, Fc regions are modified (e.g. , substituted) at one more amino acid residues. 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), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

[0100] 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.

[0101] In some embodiments, modifications to Fc regions reduce or abrogate effector functions, e.g., Fey receptor-mediated effector functions. Non-limiting examples of effectorreducing 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).

[0102] 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, and L234Y / L235Q / G236W / S239M / H268D / D270E / S298A in one chain and D270E / K326D / A330M / K334E in another chain.

[0103] 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.

[0104] 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.JDJ-073PCPRG-073WO

[0105] 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.

[0106] 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.

[0107] Amino acid sequences of exemplary Fc sequences are provided in Table 2.Table 2. Exemplary Fc SequencesJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WOJDJ-073PCPRG-073WO

[0108] In some embodiments, one or more modifications in the modified Fc region is 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, and S267D. In some embodiments, one or more modifications in the modified Fc region is selected from the group consisting of S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q3I1V, A378V, E38OA, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W.

[0109] 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 / P331S; C226S / P230S; L234A / G237A; L234A / L235A / G237A; Q311R / M428L; and L234A / L235A / P329G.

[0110] 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;JDJ-073PCPRG-073WON297A / 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 / QVV; N297A / DDRVV; D265A / DDRVV; LALA / DDRVV; LAGA / DDRVV; LALAGA / DDRVV; LALAPG / DDRVV; SP / Q31 1R / M428L;SPLE / Q311R / M428L; N297A / Q311R / M428L; D265A / Q311R / M428L;LALA / Q311R / M428L; LAGA / Q311R / M428L; LALAGA / Q311R / M428L; andLALAPG / Q311R / M428L. 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) modifications. In some embodiments, the modified Fc region comprises M252Y / S254T / T256E (YTE) modifications.

[0111] In some embodiments, provided binding proteins include modifications to improve its 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 FcyRIIIa for antibody-dependent cellular cytotoxicity (ADCC), and towards Clq for complement-dependent cytotoxicity (CDC).

[0112] In some aspects, provided binding proteins comprise 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 have improved ADCC. In some aspects, such antibodies do not comprise any fucose at position Asn 297.

[0113] In some embodiments, provided binding proteins comprise 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 the Fc region. In some embodiments, provided binding proteins comprise an Fc region with one or more amino acid substitutions at positions 239, 332, and 330.

[0114] In some embodiments, the Fc region comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 92.5%, at least 95%, at least 96%, at least 97%,JDJ-073PCPRG-073WO at least 98%, or at least 99% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 145-256.

[0115] In some embodiments, provided binding proteins comprise an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function.

[0116] In some embodiments, provided binding proteins comprise one or more alterations that improve or diminish Cl q binding and / or CDC.

[0117] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions. In certain embodiments, the one or more amino acid substitutions results in increased antibody 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.

[0118] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.

[0119] In certain embodiments, the Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb. 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.

[0120] In some embodiments, provided binding proteins comprise an extended half-life (i.e., serum half-life), e.g., in human serum or in humans. In some embodiments, provided binding proteins comprise a half-life of at least about 14, 28, 42, 56, 70, 84, 96, or more than 96 weeks. 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 aboutJDJ-073PCPRG-073WO28 days, of about 28 days to about 96 days, about 28 days to about 84 days, about 28 days to about 70 days, about 28 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 halflife 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.

[0121] In some embodiments, provided binding proteins have a half-life that is at least 20% longer than a comparator antibody. In some embodiments, the comparator antibody comprises the same complementarity determining regions and variable regions but different Fc regions, or a comparator antibody which is bivalent and monospecific but has the same complementarity determining regions and variable regions. In some embodiments, the halflife of provided binding proteins 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 comparator antibody. In some embodiments, the half-life of provided binding proteins is longer than the half-life 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

[0122] 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 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). In some 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.JDJ-073PCPRG-073WOTable 3. Characteristics (e.g., sequences) of certain reference moleculesJDJ-073PCPRG-073WOPharmaceutical Compositions

[0123] The present disclosure also includes pharmaceutical compositions that contain therapeutically effective amounts of the APRTL-binding proteins disclosed herein.JDJ-073PCPRG-073WOCompositions 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).

[0124] 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, beta-cyc lodextrin 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)).

[0125] In some embodiments, a pharmaceutical composition is citrate-free.

[0126] In some embodiments, a pharmaceutical composition may contain nanoparticles, e.g., polymeric nanoparticles, liposomes, or micelles.JDJ-073PCPRG-073WO

[0127] 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.

[0128] 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.

[0129] 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.

[0130] For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). The carrier should be stable under the conditions of manufacture and storage, and should be preserved against microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.

[0131] 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.JDJ-073PCPRG-073WO

[0132] 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.

[0133] 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.

[0134] 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).

[0135] 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, the liquid formulation may also include one or more of a buffering agent, a surfactant, and a preservative.

[0136] 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.

[0137] 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), bacteriostaticJDJ-073PCPRG-073WO water for injection (BWFI), a pH buffered solution (e.g., phosphate -buffered saline), sterile saline solution, Ringer's solution or dextrose solution.

[0138] 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.

[0139] 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.

[0140] 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.Methods of Treatment

[0141] 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 a APRIL-binding protein or a pharmaceutical composition as disclosed herein.Subjects

[0142] In certain embodiments, the subject is a mammal, such as a primate. In some embodiments, the subject is human.

[0143] The subject may be suffering from, exhibits at least one symptom of, is diagnosed with, and / or is identified as at risk of an autoimmune or inflammatory disease. Examples of such autoimmune or inflammatory diseases include, but are not limited to, IgA nephropathy, myasthenia gravis, systemic lupus erythematosus, membranous glomerulonephritis, Sjogren syndrome, lupus nephritis, immune thrombocytopenia, acquired (autoimmune) hemolytic anemia, cold agglutinin disease, autoimmune hepatitis, multiple sclerosis, pemphigus vulgaris, and rheumatoid arthritis.JDJ-073PCPRG-073WORoutes of Administration

[0144] 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.

[0145] In some embodiments, the step of administering comprises intravenous administration. In some embodiments, the step of administering comprises subcutaneous administration.Outcomes

[0146] 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.EXAMPLESExample 1: Generation of anti-huAPRIL antibodies

[0147] 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, serum was used to measure titers against huAPRIL by ELISA.

[0148] 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.JDJ-073PC PRG-073WOExample 2: Production and purification of recombinant anti-huAPRIL antibodies

[0149] 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 fgGl constant region (hfgGl -LALA / YTE; SEQ ID NO: 159) and wild-type human TgK 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

[0150] Binding affinity (KD) of antibodies to huAPRIL or cynomolgus APRIL (cyAPRIL) was determined by surface plasmon resonance using Biacore 8K+ (FIGs. 1A and IB; 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 4JDJ-073PCPRG-073WOExample 4: Blocking activity of anti-huAPRIL antibodies

[0151] 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 huAPRIL-His-FLAG preincubated with titrated anti-huAPRIL 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 and 2B, Table 5). In FIGs. 2A and 2B, 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 1.593Example 5: Functional activity of anti-huAPRIL antibodies in huTACI and huBCMA reporter assay

[0152] Anti-huAPRIL antibodies were assessed for their functional blockade of the huAPRIL-huTACI or huAPRIL-huBCMA interaction using IIUTACI-NFKB-LUC or huBCMA-NFicB-Luc cells that express luciferase reporter driven by NF B under huAPRIL stimulation. IIUTACI-NFKB-LUC or IIUBCMA-NF B-LUC cells were incubated with huAPRIL at EC so 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 and 3B, Table 6). In FIGs.JDJ-073PCPRG-073WO3A and 3B, 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 6.690OTHER EMBODIMENTS

[0153] 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

JDJ-073PCPRG-073WOWHAT IS CLAIMED IS:

1. An APRIL (a proliferation inducing ligand) -binding protein comprising a heavy chain variable domain (Vn) 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; andCDR-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; andCDR-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.

2. The APRIL-binding protein of claim 1, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 1.

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: 6;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; andCDR-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; andCDR-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; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 18.

4. The APRIL-binding protein of claim 3, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 2.JDJ-073PCPRG-073WO5. 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: 3;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; and(ii) a light chain variable domain (VL) comprising complementarity-determining 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; andCDR-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; andCDR-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; andCDR-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;JDJ-073PCPRG-073WOCDR-H2 comprising the amino acid sequence of SEQ ID NO: 15; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 16; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 17;CDR-L2 comprising the amino acid sequence AAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 18.

6. An APRIL (a proliferation inducing ligand) -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: 21 ;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 22; andCDR-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; andCDR-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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 34.

7. The APRIL-binding protein of claim 6, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 19.

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: 24;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 25; andCDR-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; andJDJ-073PC PRG-073WOCDR-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; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 36.

9. The APRIL-binding protein of claim 8, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 20.

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: 21;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 22; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 23; and(ii) a light chain variable domain (VL) comprising complementarity-determining 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; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 26;(b)(i) a heavy chain variable domain (VH) 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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 29; andJDJ-073PCPRG-073WQ(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; andCDR-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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 34; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 35;CDR-L2 comprising the amino acid sequence WAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 36.

11. 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: 39;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 40; andCDR-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; andCDR-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 ; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 52.JDJ-073PCPRG-073WO12. The APRIL-binding protein of claim 11, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 37.

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: 42;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 43; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 44;(b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 48;CDR-L2 comprising the amino acid sequence WAS; andCDR-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; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 54.

14. The APRIL-binding protein of claim 13, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 38.

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: 39;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 40; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 41; and(ii) a light chain variable domain (VL) comprising complementarity-determining 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; andJDJ-073PCPRG-073WOCDR-L3 comprising the amino acid sequence of SEQ ID NO: 44;(b)(i) a heavy chain variable domain (Vn) 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; andCDR-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; andCDR-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-H1 comprising the amino acid sequence of SEQ ID NO: 50;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 51; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 52; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 53;CDR-L2 comprising the amino acid sequence WAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 54.

16. An APRIL-binding protein comprising a heavy chain variable domain (VH) comprising complementarity-determining regions:JDJ-073PCPRG-073WO(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 57;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 58; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 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; andCDR-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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 70.

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: 55.

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: 60;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 61; andCDR-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; andCDR-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; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 72.

19. The APRIL-binding protein of claim 18, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 56.

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: 57;JDJ-073PC PRG-073WOCDR-H2 comprising the amino acid sequence of SEQ ID NO: 58; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 59; and(ii) a light chain variable domain (VL) comprising complementarity-determining 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; andCDR-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; andCDR-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; andCDR-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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 70; andJDJ-073PCPRG-073WO(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 71;CDR-L2 comprising the amino acid sequence WAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 72.

21. An APRIL-binding protein comprising a heavy chain variable domain (Vn) 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; andCDR-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; andCDR-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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 88.

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: 73.

23. The APRIL-binding protein of claim 21 or 22, further comprising 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; andCDR-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; andCDR-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; andJDJ-073PC PRG-073WOCDR-L3 comprising the amino acid sequence of SEQ ID NO: 90.

24. The APRIL-binding protein of claim 23, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 92.

25. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (Vn) comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 75;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 76; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 77; and(ii) a light chain variable domain (VL) comprising complementarity-determining 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; andCDR-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; andCDR-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; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 85; orJDJ-073PCPRG-073WO(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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 88; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 89;CDR-L2 comprising the amino acid sequence DAS; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 90.

26. 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: 93;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 94; andCDR-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; andCDR-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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 106.

27. The APRIL-binding protein of claim 26, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 91.

28. The APRIL-binding protein of claim 26 or 27, further comprising a light chain variable domain (VL) comprising complementarity-determining regions:(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 96;JDJ-073PC PRG-073WOCDR-L2 comprising the amino acid sequence of SEQ ID NO: 97; andCDR-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; andCDR-L3 comprising the amino acid sequence of 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; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 108.

29. The APRIL-binding protein of claim 28, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 92.

30. 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: 93;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 94; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 95; and(ii) a light chain variable domain (VL) comprising complementarity-determining 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; andCDR-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;JDJ-073PCPRG-073WOCDR-H2 comprising the amino acid sequence of SEQ ID NO: 100; andCDR-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; andCDR-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; andCDR-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; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 108.

31. 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: 111;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 112; andCDR-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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 119; orJDJ-073PC PRG-073WO(c) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 122;CDR-H2 comprising the amino acid sequence of SEQ ID NO: 123; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 124.

32. The APRIL-binding protein of claim 31, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 109.

33. The APRIL-binding protein of claim 31 or 32, further comprising 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; andCDR-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; andCDR-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; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 126.

34. The APRIL-binding protein of claim 3, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 110.

35. An APRIL-binding protein comprising(a)(i) a heavy chain variable domain (V H) 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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 113; andJDJ-073PCPRG-073WQ(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 114;CDR-L2 comprising the amino acid sequence of SEQ ID NO: 1 15; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 1 16;(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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 1 19; 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; andCDR-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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 124; and(ii) a light chain variable domain (VL) comprising complementarity-determining regions:CDR-L1 comprising the amino acid sequence of SEQ ID NO: 125;CDR-L2 comprising the amino acid sequence DAS; andJDJ-073PCPRG-073WOCDR-L3 comprising the amino acid sequence of SEQ ID NO: 126.

36. 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: 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.

37. The APRIL-binding protein of claim 36, wherein the VH comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 127.

38. The APRIL-binding protein of claim 36 or 37, further comprising 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; andCDR-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; andCDR-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; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 144.

39. The APRIL-binding protein of claim 39, wherein the VL comprises an amino acid sequence that is at least 85% identical to that of SEQ ID NO: 128.

40. An APRIL- binding protein comprisingJDJ-073PCPRG-073WO(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; andCDR-H3 comprising the amino acid sequence of SEQ ID NO: 131 ; and(ii) a light chain variable domain (VL) comprising complementarity-determining 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; andCDR-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; andCDR-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; andCDR-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 ; andJDJ-073PCPRG-073WOCDR-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; andCDR-L3 comprising the amino acid sequence of SEQ ID NO: 144.

40. The APRIL-binding protein of any one of claims 1-39, wherein the APRIL binding protein is an antibody or antigen-binding fragment thereof.

41. The APRIL-binding protein of claim 40, wherein the APRIL binding protein is a human antibody or antigen-binding fragment thereof.

42. The APRIL-binding protein of claim 40 or 41 , 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.

43. The APRIL-binding protein of any one of claims 1-42, wherein the antibody or antigen binding fragment thereof comprises an Fc region.

44. The APRIL-binding protein of claim 43, wherein the Fc region is an IgGl, IgG2, or IgG4 Fc region.

45. The APRIL-binding protein of claim 44, wherein the Fc region is a modified Fc region.

46. The APRIL-binding protein of claim 45, wherein the modified Fc region comprises a half-life extending mutation or set of mutations.

47. The APRIL-binding protein of claim 46, 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).JDJ-073PCPRG-073WO48. An isolated nucleic acid encoding an APRIL-binding protein of any one of claims 1-47.

49. An expression vector comprising the isolated nucleic acid of claim 48.

50. A host cell comprising the isolated nucleic acid molecule of claim 48 or the expression vector of claim 49.

51. A pharmaceutical composition comprising the APRIL-binding protein of any one of claims 1-47 and a pharmaceutically acceptable carrier.

52. 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 -48 or the pharmaceutical composition of claim 51.

53. The method of claim 52, wherein the subject has an autoimmune or inflammatory disease.

54. The method of claim 53, wherein the subject has a disorder selected from the group consisting of IgA nephropathy, myasthenia gravis, systemic lupus erythematosus, membranous glomerulonephritis, Sjogren syndrome, lupus nephritis, immune thrombocytopenia, acquired (autoimmune) hemolytic anemia, cold agglutinin disease, autoimmune hepatitis, multiple sclerosis, pemphigus vulgaris, and rheumatoid arthritis.

55. The method of any one of claims 52-54, wherein the step of administering comprises systemic administration of the APRIL-binding protein.

56. The method of claim 55, wherein the systemic administration comprises intravenous or subcutaneous administration.

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