Complement factor H-associated 4 specific antibodies and uses thereof

Abstract

The present disclosure relates to the treatment and / or prevention of age-related macular degeneration (AMD), including advanced forms of dry AMD referred to as geomorphic atrophy (GA). In particular, the present disclosure provides novel therapeutic antibodies that target alternative pathway components of the complement activation system, including complement factor H-related (CFHR) 4.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 336,751, filed April 29, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0003] Sequence Listing

[0004] The accompanying computer-readable sequence list text, titled "40186_601_SequenceListing", created on March 30, 2023, with a file size of 643,199 bytes, is hereby incorporated in its entirety by reference. Technical Field

[0005] The embodiments disclosed herein relate to the treatment and / or prevention of age-related macular degeneration (AMD), including advanced forms of dry AMD known as geographic atrophy (GA). Specifically, this disclosure provides novel therapeutic antibodies that target alternative pathway components of the complement activation system, including complement factor H-related (CFHR) 4. Background Technology

[0006] Age-related macular degeneration (AMD) is the leading cause of severe vision loss in adults over 50. The U.S. Centers for Disease Control and Prevention estimates that 1.8 million people have AMD, and another 7.3 million are at great risk of losing their vision due to it. This eye disease occurs when the macula (the small part of the retina located at the back of the inner side of the eyeball) changes. AMD is a form of central vision loss that can occur in two forms: "dry" (atrophic) and "wet" (exudative). Most people with macular degeneration have the dry form. Geographic atrophy (GA) is considered a late stage of the dry form of AMD, characterized by localized and progressive loss of photoreceptors. GA is less common than neovascular AMD and accounts for 10-20% of legally recognized blindness cases, affecting more than 5 million people worldwide. Currently, there are no approved or effective treatments to prevent the onset or progression of GA; however, significant advances in understanding the pathogenesis of GA in recent years have led to many new potential therapies.

[0007] Genetic and molecular studies have identified the complement system as a crucial factor in the etiology and progression of AMD. Many genetic risk variants cluster in genes involved in alternative complement pathways, and complement activation products are elevated in AMD patients. However, attempts to treat AMD with complement modulators have not been successful, suggesting its complexity cannot be predicted solely from a genetic perspective. Therefore, new treatments for AMD and GA remain needed. Summary of the Invention

[0008] Embodiments of this disclosure include antibodies against complement factor H-related 4 (CFHR4) peptide, or antigen-binding fragments thereof. According to these embodiments, this disclosure provides heavy chain variable regions (VH) comprising complementation-determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and light chain variable regions (VL) comprising complementation-determining regions (CDRs) LCDR1, LCDR2, and LCDR3. In some embodiments, HCDR1 comprises one of the following amino acid sequences: (a) X1YX2X3X4 (SEQ ID NO: 1), wherein X1 is S, T, G, or N; X2 is G or Y; X3 is I or M; and X4 is S, H, or Q; (b) X1YX2X3X4 (SEQ ID NO: 21), wherein X1 is S, T, R, or D; X2 is T, V, A, G, S, or E; X3 is M or I; and X4 is N, S, or H; (c) X1X2X3WX4X5 (SEQ ID NO: 53), wherein X1 is T, S, G, or I; X2 is S, R, Y, or H; X3 is D, N, H, K, or Y; X4 is W or S; and X5 is T or S; or (d) SNX1AX2WN (SEQ ID NO: 88), wherein X1 is S, T, or N; and X2 is A or S. In some embodiments, HCDR2 comprises one of the following amino acid sequences: (a) X1X2X3X4X5GX6TX7X8X9X 10 X 11 X 12 QX 13 (SEQ ID NO: 8), wherein X1 is W or I; X2 is S, N or D; X3 is A or P; X4 is Y, N or S; X5 is N, G or S; X6 is N, S or G; X7 is N, H, T or S; X8 is Y or N; X9 is A or Y; X 10 For Q or A; X 11 For K or S; X 12 For L or F; X 13 (a) G or D; (b) X1IX2X3X4X5X6X7X8X9X 10 X 11 DX 12 VX 13 G (SEQ ID NO: 32), wherein X1 is S, V, Y, G, or D; X2 is S or W; X3 is S, V, G, H, or W; X4 is S, D, N, or T; X5 is S or G; X6 is S or G; X7 is Y, S, T, or R; X8 is T, K, I, or V; X9 is Y, F, N, or G; X 10 For Y or H; X 11 For A or V; X 12 For S or P; X 13For R, K, or T; (c)X1X2X3X4X5GX6X7X8X9X 10 PLSX 11 S (SEQ ID NO: 65), wherein X1 is E or Y; X2 is I, T or V; X3 is Y, H or F; X4 is H or Y; X5 is S, D, T, G; X6 is S, T, G or N; X7 is T or I; X8 is N or K; X9 is Y, K or S; X 10 For N, S, K, or H; X 11 For K or Q; or (d) X1TX2YRSX3X4X5X6X7X8X9X 10 SX 11 X 12 S (SEQ ID NO: 102), wherein X1 is R, T, M, or K; X2 is Y or F; X3 is K or R; X4 is W or L; X5 is F, Y, or S; X6 is N, S, D, or A; X7 is N, V, G, D, Y, or A; X8 is Y or F; X9 is S, A, or P; X 10 V, L, or A; X 11 For V or M; X 12 It is K or S. In some embodiments, HCDR3 contains one of the following amino acid sequences: (a) SEQ ID NO: 15-20; (b) SEQ ID NO: 43-52; (c) SEQ ID NO: 77-87; or (d) SEQ ID NO: 116-128.

[0009] According to the above embodiments, the LCDR1 of the anti-CFHR4 antibody disclosed herein contains the amino acid sequence of any one of SEQ ID NO: 130-151, SEQ ID NO: 198-199, SEQ ID NO: 207-215 or SEQ ID NO: 237-243; the LCDR2 contains the amino acid sequence of any one of SEQ ID NO: 153-174, SEQ ID NO: 201-202, SEQ ID NO: 217-225 or SEQ ID NO: 245-251; and the LCDR3 contains the amino acid sequence of any one of SEQ ID NO: 175-196, SEQ ID NO: 204-205, SEQ ID NO: 227-235 or SEQ ID NO: 253-259.

[0010] In some embodiments, this disclosure provides an antibody against the CFHR4 peptide or an antigen-binding fragment thereof, comprising a VH containing complementarity-determining regions HCDR1, HCDR2, and HCDR3, and a VL containing complementarity-determining regions LCDR1, LCDR2, and LCDR3, wherein LCDR1 contains one of the following amino acid sequences: (a) RX1SX2X3X4X5X6X7LX8 (SEQ ID NO: 129), wherein X1 is A or T; X2 is Q or K; X3 is G, S, D, or N; X4 is I, F, or V; X5 is T, R, A, S, N, G, or I; X6 is T, N, G, S, I, K, or Y; X7 is W, D, or Y; X8 is A, T, G, N, or D; (b) RSSQX1LLHSX2GYNX3LD (SEQ ID NO: 197), wherein X1 is S or R; X2 is T or S; X3 is F or Y; (c) RASQX1X2X3X4X5X6X7X8A (SEQ ID NO: 206), wherein X1 is S, N or T; X2 is V or I; X3 is S or R; X4 is S, G or N; X5 is N or S; X6 is L or Y; X7 is A, L or V; or (d) SEQ ID NO: 236. In some embodiments, LCDR2 comprises one of the following amino acid sequences: (a) X1X2SX3LX4X5 (SEQ ID NO: 152), wherein X1 is G, A, T, or K; X2 is A or T; X3 is S, T, G, or N; X4 is E, Q, or L; and X5 is S, T, or G; (b) LX1SX2RAS (SEQ ID NO: 200), wherein X1 is A or G; and X2 is N or S; (c) GASX1RAT (SEQ ID NO: 216), wherein X1 is T, S, or N; or (d) WASX1RES (SEQ ID NO: 244), wherein X1 is T, P, or N. In some embodiments, LCDR3 comprises one of the following amino acid sequences: (a) SEQ ID NO: 175-196; (b) MQX1LQTPX2T (SEQ ID NO: 203), wherein X1 is A or G; X2 is Y or P; (c) QX1YX2X3X4X5X6T (SEQ ID NO: 226), wherein X1 is Q or H; X2 is D or G; X3 is N, S or R; X4 is W or S; X5 is R, P, F, Y, V or I; X6 is T, W, L or I; or (d) QQX1X2X3X4PX5X6T (SEQ ID NO: 252), wherein X1 is Y or F; X2 is G or Y; X3 is S or N; X4 is S, T or I; X5 is M, Y or R; X6 is Y or T.

[0011] According to the above embodiments, the HCDR1 of the anti-CFHR4 antibody disclosed herein contains the amino acid sequence of any one of SEQ ID NO: 2-7, SEQ ID NO: 22-31, SEQ ID NO: 54-64 or SEQ ID NO: 89-101; the HCDR2 contains the amino acid sequence of any one of SEQ ID NO: 9-14, SEQ ID NO: 33-42, SEQ ID NO: 66-76 or SEQ ID NO: 103-115; and the HCDR3 contains the amino acid sequence of any one of SEQ ID NO: 15-20, SEQ ID NO: 43-52, SEQ ID NO: 77-87 or SEQ ID NO: 116-128.

[0012] In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 2; HCDR2 comprises the amino acid sequence of SEQ ID NO: 9; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 10; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; HCDR2 comprises the amino acid sequence of SEQ ID NO: 11; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 5; HCDR2 comprises the amino acid sequence of SEQ ID NO: 12; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 18. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 6; HCDR2 comprises the amino acid sequence of SEQ ID NO: 13; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 19. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 22; HCDR2 comprises the amino acid sequence of SEQ ID NO: 33; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 43. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 23; HCDR2 comprises the amino acid sequence of SEQ ID NO: 34; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 44. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 24; HCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 45. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 25; HCDR2 comprises the amino acid sequence of SEQ ID NO: 36; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 46. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 26; HCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 47.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 27; HCDR2 comprises the amino acid sequence of SEQ ID NO: 38; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 28; HCDR2 comprises the amino acid sequence of SEQ ID NO: 39; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 49. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 29; HCDR2 comprises the amino acid sequence of SEQ ID NO: 40; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 50. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 30; HCDR2 comprises the amino acid sequence of SEQ ID NO: 41; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 51. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 31; HCDR2 comprises the amino acid sequence of SEQ ID NO: 42; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 54; HCDR2 comprises the amino acid sequence of SEQ ID NO: 66; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 77. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 55; HCDR2 comprises the amino acid sequence of SEQ ID NO: 67; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 78. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 56; HCDR2 comprises the amino acid sequence of SEQ ID NO: 68; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 79. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 57; HCDR2 comprises the amino acid sequence of SEQ ID NO: 69; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 80. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 58; HCDR2 comprises the amino acid sequence of SEQ ID NO: 70; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 81.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 59; HCDR2 comprises the amino acid sequence of SEQ ID NO: 71; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 82. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 60; HCDR2 comprises the amino acid sequence of SEQ ID NO: 72; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 83. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 61; HCDR2 comprises the amino acid sequence of SEQ ID NO: 73; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 84. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; HCDR2 comprises the amino acid sequence of SEQ ID NO: 74; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 85. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 63; HCDR2 comprises the amino acid sequence of SEQ ID NO: 75; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 86. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 64; HCDR2 comprises the amino acid sequence of SEQ ID NO: 76; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 87. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 89; HCDR2 comprises the amino acid sequence of SEQ ID NO: 103; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 116. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 90; HCDR2 comprises the amino acid sequence of SEQ ID NO: 104; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 91; HCDR2 comprises the amino acid sequence of SEQ ID NO: 105; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 118. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 92; HCDR2 comprises the amino acid sequence of SEQ ID NO: 106; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 119.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 93; HCDR2 comprises the amino acid sequence of SEQ ID NO: 107; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 120. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 94; HCDR2 comprises the amino acid sequence of SEQ ID NO: 108; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 121. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 95; HCDR2 comprises the amino acid sequence of SEQ ID NO: 109; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 122. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 96; HCDR2 comprises the amino acid sequence of SEQ ID NO: 110; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 123. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 97; HCDR2 comprises the amino acid sequence of SEQ ID NO: 111; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 124. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 98; HCDR2 comprises the amino acid sequence of SEQ ID NO: 112; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 125. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 99; HCDR2 comprises the amino acid sequence of SEQ ID NO: 113; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 126. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 100; HCDR2 comprises the amino acid sequence of SEQ ID NO: 114; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 127. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 101; HCDR2 comprises the amino acid sequence of SEQ ID NO: 115; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 128. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 130; LCDR2 comprises the amino acid sequence of SEQ ID NO: 153; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 175.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 131; LCDR2 comprises the amino acid sequence of SEQ ID NO: 154; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 176. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 132; LCDR2 comprises the amino acid sequence of SEQ ID NO: 155; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 177. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 133; LCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 178. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 134; LCDR2 comprises the amino acid sequence of SEQ ID NO: 157; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 179. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 135; LCDR2 comprises the amino acid sequence of SEQ ID NO: 158; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 180. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 136; LCDR2 comprises the amino acid sequence of SEQ ID NO: 159; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 181. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 137; LCDR2 comprises the amino acid sequence of SEQ ID NO: 160; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 182. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 138; LCDR2 comprises the amino acid sequence of SEQ ID NO: 161; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 183. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 139; LCDR2 comprises the amino acid sequence of SEQ ID NO: 162; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 184. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 140; LCDR2 comprises the amino acid sequence of SEQ ID NO: 163; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 185.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 141; LCDR2 comprises the amino acid sequence of SEQ ID NO: 164; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 186. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 142; LCDR2 comprises the amino acid sequence of SEQ ID NO: 165; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 187. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 143; LCDR2 comprises the amino acid sequence of SEQ ID NO: 166; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 188. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 144; LCDR2 comprises the amino acid sequence of SEQ ID NO: 167; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 189. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 145; LCDR2 comprises the amino acid sequence of SEQ ID NO: 168; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 190. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 146; LCDR2 comprises the amino acid sequence of SEQ ID NO: 169; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 191. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 147; LCDR2 comprises the amino acid sequence of SEQ ID NO: 170; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 192. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 148; LCDR2 comprises the amino acid sequence of SEQ ID NO: 171; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 193. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 149; LCDR2 comprises the amino acid sequence of SEQ ID NO: 172; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 194. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 150; LCDR2 comprises the amino acid sequence of SEQ ID NO: 173; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 195.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 151; LCDR2 comprises the amino acid sequence of SEQ ID NO: 174; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 196. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 198; LCDR2 comprises the amino acid sequence of SEQ ID NO: 201; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 204. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 199; LCDR2 comprises the amino acid sequence of SEQ ID NO: 202; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 205. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 207; LCDR2 comprises the amino acid sequence of SEQ ID NO: 217; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 227. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 208; LCDR2 comprises the amino acid sequence of SEQ ID NO: 218; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 228. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 209; LCDR2 comprises the amino acid sequence of SEQ ID NO: 219; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 229. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 210; LCDR2 comprises the amino acid sequence of SEQ ID NO: 220; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 230. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 211; LCDR2 comprises the amino acid sequence of SEQ ID NO: 221; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 231. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 212; LCDR2 comprises the amino acid sequence of SEQ ID NO: 222; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 232. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 213; LCDR2 comprises the amino acid sequence of SEQ ID NO: 223; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 233.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 214; LCDR2 comprises the amino acid sequence of SEQ ID NO: 224; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 234. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 215; LCDR2 comprises the amino acid sequence of SEQ ID NO: 225; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 235. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 237; LCDR2 comprises the amino acid sequence of SEQ ID NO: 245; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 253. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 238; LCDR2 comprises the amino acid sequence of SEQ ID NO: 246; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 254. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 239; LCDR2 comprises the amino acid sequence of SEQ ID NO: 247; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 255. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 240; LCDR2 comprises the amino acid sequence of SEQ ID NO: 248; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 256. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 241; LCDR2 comprises the amino acid sequence of SEQ ID NO: 249; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 257. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 242; LCDR2 comprises the amino acid sequence of SEQ ID NO: 250; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 258. In some embodiments, LCDR1 contains the amino acid sequence of SEQ ID NO: 243; LCDR2 contains the amino acid sequence of SEQ ID NO: 251; and LCDR3 contains the amino acid sequence of SEQ ID NO: 259.

[0013] In some embodiments, the VH of the anti-CFHR4 antibody of this disclosure comprises an amino acid sequence having at least 90% identity with any of the following: (a) SEQ ID NO: 260-265; (b) SEQ ID NO: 284-293; (c) SEQ ID NO: 324-334 or (d) SEQ ID NO: 368-380. In some embodiments, the VL of the anti-CFHR4 antibody of this disclosure comprises an amino acid sequence having at least 90% identity with any of the following: (a) SEQ ID NO: 272-277; (b) SEQ ID NO: 304-313; (c) SEQ ID NO: 346-356 or (d) SEQ ID NO: 394-406. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 260, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 272. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 261, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 273. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 262, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 274. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 263, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 275. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 264, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 276. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 265, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 277. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 284, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 304. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 285, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 305.In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 286, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 306. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 287, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 307. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 288, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 308. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 289, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 309. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 290, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 310. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 291, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 311. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 292, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 312. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 293, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 313. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 324, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 346. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 325, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 347. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 326, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 348. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 327, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 349.In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 328, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 350. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 329, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 351. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 330, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 352. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 331, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 353. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 332, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 354. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 333, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 354. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 334, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 356. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 368, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 394. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 369, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 395. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 370, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 396. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 371, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 397. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 372, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 398.In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 373, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 399. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 374, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 400. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 375, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 401. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 376, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 402. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 377, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 403. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 378, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 404. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 379, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 405. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 380, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 406.

[0014] According to the above embodiments, this disclosure provides anti-CFHR4 antibodies comprising various functional features. In some embodiments, the anti-CFHR4 antibodies described herein bind to the antigen or a variant or isoform of CFHR4 (SEQ ID NO: 580) (via interaction with its antigenic determinant (epitope). In some embodiments, binding of the anti-CFHR4 antibody to CFHR4 reduces complement activation. In some embodiments, the anti-CFHR4 antibody is present at about 100 nM or less. KD Combined with human CFHR4b ( Figure 6 ).

[0015] In some embodiments, the anti-CFHR4 antibody attenuates complement component 3 (C3) convertase activity. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 330, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 352. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 293, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 313. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 378, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 404. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 377, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 403. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 376, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 402. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 289, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 309. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 371, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 397. In some embodiments, VH comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 284, and VL comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 304.

[0016] In some embodiments, the antibody cross-reacts with the cynomolgus monkey CFHR4b protein (cCFHR4b). In some embodiments, the antibody comprises VH and VL regions having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-560, ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-569, ATX-P-570, ATX-P-571, and ATX-P-572. 3. ATX-P-574, ATX-P-576, ATX-P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX- P-583, ATX-P-587, ATX-P-588, ATX-P-591, ATX-P-592, ATX-P-594, ATX-P-596, ATX-P-600 and ATX-P-604.

[0017] In some embodiments, the antibody does not cross-react with the cynomolgus monkey CFHR4b protein (cCFHR4b). In some embodiments, the antibody comprises VH and VL regions having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-572, ATX-P-595, ATX-P-597, ATX-P-598, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-607, ATX-P-608, ATX-P-609, and ATX-P-610.

[0018] In some embodiments, the antibody cross-reacts with complement factor H-related protein 4a (CFHR4a). In some embodiments, the antibody comprises VH and VL regions having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-560, ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-569, ATX-P-570, ATX-P-571, ATX-P-572, ATX-P-573, ATX-P-574, ATX-P-576, ATX-P-577, and ATX-P-577. 8. ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX-P-583, ATX-P-587, ATX-P-588, ATX-P-591, ATX-P-592, ATX-P-594, ATX-P-595 , ATX-P-596, ATX-P-597, ATX-P-600, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-604, ATX-P-607, ATX-P-608, ATX-P-609 and ATX-P-610.

[0019] In some embodiments, the antibody does not cross-react with complement factor H-related protein 4a (CFHR4a). In some embodiments, the antibody comprises VH and VL regions that are at least 90% identical to ATX-P-598.

[0020] In some embodiments, the antibody cross-reacts with complement factor H-related protein 3 (CFHR3). In some embodiments, the antibody comprises a VH region and a VL region having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-569, ATX-P-572, ATX-P-573, ATX-P-574, ATX-P-576, ATX... -P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-583, ATX-P-587, ATX-P-588, ATX-P-592, A TX-P-594, ATX-P-595, ATX-P-596, ATX-P-600, ATX-P-603, ATX-P-604, ATX-P-608, ATX-P-609 and ATX-P-610.

[0021] In some embodiments, the antibody does not cross-react with complement factor H-related protein 3 (CFHR3). In some embodiments, the antibody comprises a VH region and a VL region having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-560, ATX-P-570, ATX-P-571, ATX-P-582, ATX-P-591, ATX-P-597, ATX-P-598, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-604, and ATX-P-607.

[0022] In some embodiments, the antibody cross-reacts with complement factor H-related protein 1 (CFHL1). In some embodiments, the antibody comprises a VH and VL region having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-570, ATX-P-571, ATX-P-573, and ATX-P-574. 4. ATX-P-576, ATX-P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX-P-583 , ATX-P-587, ATX-P-588, ATX-P-591, ATX-P-594, ATX-P-595, ATX-P-596, ATX-P-600 and ATX-P-604.

[0023] In some embodiments, the antibody does not cross-react with complement factor H-related protein 1 (CFHL1). In some embodiments, the antibody comprises VH and VL regions having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-560, ATX-P-569, ATX-P-572, ATX-P-592, ATX-P-597, ATX-P-598, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-607, ATX-P-608, ATX-P-609, and ATX-P-610.

[0024] According to the above embodiments, the anti-CFHR4 antibody of this disclosure can be a monoclonal antibody, a human antibody, a humanized antibody, and / or a chimeric antibody. In some embodiments, the antibody is a fragment selected from the group consisting of: Fab, Fab-C, Fab′-SH, Fv, scFv, and (Fab′)2 fragments. In some embodiments, the anti-CFHR4 antibody is a monospecific antibody. In some embodiments, the anti-CFHR4 antibody is a bispecific antibody. In some embodiments, the anti-CFHR4 antibody comprises two or more single-domain antibodies, said single-domain antibodies forming bivalent, trivalent, or quadrivalent antibodies that recognize different epitopes on the same or different antigens.

[0025] In some embodiments, the antibody includes a detection portion. In some embodiments, the antibody includes a purification portion. In some embodiments, the antibody includes a half-life extension portion. In some embodiments, the half-life extension portion comprises a polypeptide of at least 20 amino acids in length and containing any combination of G, A, S, T, E, and P residues. In some embodiments, the half-life extension polypeptide is linked to the C-terminus or N-terminus of the antibody.

[0026] The anti-CFHR4 antibody disclosed herein can be administered as part of a pharmaceutical composition in a therapeutically effective amount to treat ocular diseases (e.g., AMD or GA). In some embodiments, the composition is suitable for ocular administration. In some embodiments, ocular administration includes injection into the vitreous fluid. In some embodiments, ocular administration includes delivery of the antibody using conjunctival inserts, contact lenses, gels, nanoparticles, mucosal adhesion polymers, ointments, solutions, suspensions, eye drops, and / or implants.

[0027] Embodiments of this disclosure also include methods for treating and / or preventing AMD and / or GA. According to these embodiments, the method includes administering a pharmaceutical composition comprising a therapeutically effective amount of the disclosed anti-CFHR4 antibody. In some embodiments, the pharmaceutical composition is administered ocularly and treats at least one AMD symptom. In some embodiments, AMD includes wet AMD. In some embodiments, AMD includes dry AMD (e.g., GA). In some embodiments, at least one AMD symptom includes visual distortion, decreased central vision, blurred vision, and / or difficulty adapting to low light. In some embodiments, administering the pharmaceutical composition reduces complement activation in the subject's eye. In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of the disclosed anti-CFHR4 antibody is administered at a dose ranging from about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, the pharmaceutical composition is administered at a dose ranging from about 0.0001 mg / ml to about 100 mg / ml.

[0028] Embodiments of this disclosure also include a polynucleotide encoding any anti-CFHR4 antibody of this disclosure. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 381-393. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 380-393. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419.

[0029] In some embodiments, the polynucleotide encoding the anti-CFHR4 antibody of this disclosure comprises: (a) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 266 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 278; (b) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 267 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 279; (c) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 268 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 280; (d) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 269 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 281; (e) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 270 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 282; or (f) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 270 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 282; or (f) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 270 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 282. 270 is a nucleic acid sequence with at least 70% identity and a nucleic acid sequence with at least 70% identity to SEQ ID NO: 283.

[0030] In some embodiments, the polynucleotide encoding the anti-CFHR4 antibody of this disclosure comprises: (a) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 294 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 314; (b) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 295 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 315; (c) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 296 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 316; (d) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 297 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 317; (e) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 298 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 318; (f) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 299 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 318. (g) A nucleic acid sequence with at least 70% identity to SEQ ID NO: 319; (h) A nucleic acid sequence with at least 70% identity to SEQ ID NO: 300 and a nucleic acid sequence with at least 70% identity to SEQ ID NO: 320; (h) A nucleic acid sequence with at least 70% identity to SEQ ID NO: 301 and a nucleic acid sequence with at least 70% identity to SEQ ID NO: 321; (i) A nucleic acid sequence with at least 70% identity to SEQ ID NO: 302 and a nucleic acid sequence with at least 70% identity to SEQ ID NO: 322; or (j) A nucleic acid sequence with at least 70% identity to SEQ ID NO: 303 and a nucleic acid sequence with at least 70% identity to SEQ ID NO: 323.

[0031] In some embodiments, the polynucleotide encoding the anti-CFHR4 antibody of this disclosure comprises: (a) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 335 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 357; (b) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 336 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 358; (c) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 337 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 359; (d) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 338 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 360; (e) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 339 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 361; (f) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 340 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 357. (g) A nucleic acid sequence with at least 70% identity to SEQ ID NO: 362; (h) A nucleic acid sequence with at least 70% identity to SEQ ID NO: 341 and a nucleic acid sequence with at least 70% identity to SEQ ID NO: 363; (h) A nucleic acid sequence with at least 70% identity to SEQ ID NO: 342 and a nucleic acid sequence with at least 70% identity to SEQ ID NO: 364; (i) A nucleic acid sequence with at least 70% identity to SEQ ID NO: 343 and a nucleic acid sequence with at least 70% identity to SEQ ID NO: 365; (j) A nucleic acid sequence with at least 70% identity to SEQ ID NO: 344 and a nucleic acid sequence with at least 70% identity to SEQ ID NO: 366; or (k) A nucleic acid sequence with at least 70% identity to SEQ ID NO: 345 and a nucleic acid sequence with at least 70% identity to SEQ ID NO: 367.

[0032] In some embodiments, the polynucleotide encoding the anti-CFHR4 antibody of this disclosure comprises: (a) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 381 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 407; (b) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 382 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 408; (c) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 383 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 409; (d) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 384 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 410; (e) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 385 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 411; (f) a nucleic acid sequence having at least 70% identity with SEQ ID NO: 386 and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 407. (g) Nucleic acid sequences with at least 70% identity to SEQ ID NO: 412; (h) Nucleic acid sequences with at least 70% identity to SEQ ID NO: 387 and SEQ ID NO: 413; (h) Nucleic acid sequences with at least 70% identity to SEQ ID NO: 388 and SEQ ID NO: 414; (i) Nucleic acid sequences with at least 70% identity to SEQ ID NO: 389 and SEQ ID NO: 415; (j) Nucleic acid sequences with at least 70% identity to SEQ ID NO: 390 and SEQ ID NO: 416; (k) Nucleic acid sequences with at least 70% identity to SEQ ID NO: 391 and SEQ ID NO: 417; (l) Nucleic acid sequences with at least 70% identity to SEQ ID NO: 392 and SEQ ID NO: 413; The nucleic acid sequence with at least 70% identity to SEQ ID NO: 418; or (m) the nucleic acid sequence with at least 70% identity to SEQ ID NO: 393 and the nucleic acid sequence with at least 70% identity to SEQ ID NO: 419.

[0033] According to these embodiments, this disclosure includes expression vectors comprising any polynucleotide encoding an anti-CFHR4 antibody of this disclosure. In some embodiments, the expression vector is adapted to manufacture the anti-CFHR4 antibody of this disclosure for delivery to a subject. In some embodiments, the expression vector is suitable for gene therapy (e.g., an expression vector for delivering a polynucleotide encoding an anti-CFHR4 antibody of this disclosure to a subject). In some embodiments, the expression vector is an adeno-associated virus (AAV) vector or contains an AAV backbone. In some embodiments, the expression vector is a lentiviral vector (LV) or contains an LV backbone. In some embodiments, the expression vector is a herpes simplex virus (HSV) vector or a retroviral vector.

[0034] According to these embodiments, this disclosure also provides a method of administering ocular gene therapy to a subject in need, the method comprising injecting a pharmaceutical composition comprising an effective amount of the expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-CFHR4 antibody of this disclosure). According to these embodiments, this disclosure also provides a method of treating AMD and / or GA, the method comprising administering a pharmaceutical composition comprising an effective amount of the expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-CFHR4 antibody of this disclosure). In some embodiments, administering the pharmaceutical composition treats at least one symptom of AMD and / or GA. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 A representative illustration of the molecular mechanisms underlying the treatment of advanced age-related macular degeneration (AMD), including geographic atrophy (GA), using the anti-CFHR4 antibody disclosed herein.

[0036] Figure 2 When a deletion (labeled by one of the two variants) or a pQTL variant exists on the Y402 haplotype, the odds ratios and confidence intervals for the haplotype effect are plotted (see Table 1). Associations are performed against a reference haplotype with OR=1.

[0037] Figures 3A to 3C According to three different immunization regimens / cohorts ( Figure 3A - Queue 1; Figure 3B - Queue 2; Figure 3C - Cohort 3), used to determine representative ELISA results for antigen-positive serum titers in mice immunized with CFHR4.

[0038] Figure 4Representative results of the thermostability of the human CFHR4 monoclonal antibody disclosed herein (see Table 2, “ATX” antibody). Thermostability was assessed by differential scanning fluorometry (DSF) using protein thermal shift (PTS) assay.

[0039] Figures 5A to 5B Representative results from CFHR4 antibody cross-blocking assays, including representative heatmap data analyzing the ability of antibodies to block each other from binding to antigens. Figure 5A ), and a representative network diagram that gradually groups antibodies with similar competitive characteristics.

[0040] Figure 6 Representative results of CFHR4 antibody binding kinetics.

[0041] Figure 7 Representative results of cross-reactivity of CFHR4 antibody with cynomolgus monkey CFHR4b protein (cCFHR4b).

[0042] Figure 8 Representative results of cross-reactivity with CFHR4 antibody against human CFHR4a protein.

[0043] Figure 9 Representative results of cross-reactivity with CFHR4 antibody against human CFHR3 protein.

[0044] Figure 10 Representative results of cross-reactivity of CFHR4 antibody with human CFHL-1 (Y402H) protein.

[0045] Figures 11A to 11D : A representative schematic diagram of the C3 convertase assembly assay used to evaluate the ability of the CFHR4 antibody of this disclosure to affect C3 convertase formation ( Figure 11A ). Figure 11B Representative dose-response curves for top-tier inhibitory CFHR4 antibodies, and Figure 11C Including targeting Figure 11B The IC50 value was calculated for each antibody tested. Figure 11D A representative summary of data for anti-CFHR4 antibodies, showcasing at least three functional classes, is provided. DETAILED DESCRIPTION

[0046] The embodiments disclosed herein relate to the treatment and / or prevention of age-related macular degeneration (AMD), including advanced forms of dry AMD known as geographic atrophy (GA). Specifically, this disclosure provides novel therapeutic antibodies that target alternative pathway components of the complement activation system, including complement factor H-related (CFHR) 4.

[0047] Human complement factor H-associated protein (CFHR) 4 belongs to the plasma glycoprotein factor H family, which consists of short shared repeat (SCR) domains. Although factor H is a well-known inhibitor of the alternative complement pathway, the function of CFHR proteins remains unclear. For example, CFHR4 lacks an SCR homologous to the complement-inhibitory domain of factor H; however, its complement regulatory activity is not fully understood. Previous studies have demonstrated that CFHR4 binds to C-reactive protein via its N-terminal SCR, leading to activation of the classical complement pathway. CFHR4 binds to C3b via its C-terminus, but the significance of this interaction is not fully understood. Recent reports suggest that CFHR4 can serve as a platform for the assembly of C3 convertases via the alternative pathway by binding to C3b. This is at least in part based on the ability of CFHR4-bound C3b to persistently bind factor B and serum sterilization proteins, thereby generating an active convertase that produces C3a and C3b from C3. Compared to C3bBb convertases, CFHR4-C3bBb convertases are less sensitive to factor H-mediated decay. CFHR4 mutants containing conserved residue exchanges at the C-terminal C3b binding site showed significantly reduced C3b binding and alternative pathway complement activation. These preliminary data suggest that, in contrast to complement repressor H, CFHR4 acts as an enhancer of opsonization by promoting complement activation.

[0048] Complement is a powerful effector system in the innate immune system, playing a crucial role in eliminating microbes, inflammatory processes, handling cellular debris, and regulating adaptive immunity. Multilevel regulation ensures complement activation at dangerous surfaces but prevents it from having detrimental effects on host cells and tissues. This is achieved through the expression of complement inhibitors on host cell surfaces and the absence of complement inhibitors on foreign or altered self-surfaces, as well as through soluble modulators with different binding specificities to different surfaces. Plasma glycoprotein factor H (FH) is a major soluble inhibitor of the alternative complement pathway (AP). It prevents the formation of AP C3 convertase C3bBb by blocking the binding of factor B (FB) to C3b and accelerates the decay of existing C3 convertases by substituting Bb. It also acts as a cofactor for serine protease factor I (FI), cleaving C3b into inactive C3b (iC3b), which can no longer form convertases. Through these mechanisms, FH inhibits complement cascade amplification in the fluid phase and on host cell surfaces. The human factor H protein family consists of FH, its splice variant complement factor H-like protein 1 (CFHL1), and five complement factor H-related proteins (CFHR1–CFHR5) encoded by separate genes. FH comprises 20 short shared repeat (SCR) domains, CFHL1 contains SCR1–7 of FH, and CFHR proteins consist of four to nine SCRs homologous to the various domains of FH. Although CFHL1 shares the complement-inhibiting activity of FH, the physiological role of CFHR proteins is not fully understood.

[0049] CFHR4 is detected in human plasma as two distinct glycoproteins. The long isoform, 86 kDa, called CFHR4A, consists of nine segmented cytokines (SCRs). The shorter isoform, approximately 45 kDa, called CFHR4B, consists of five SCRs representing CFHR4A: SCR1 and SCR6–9. In CFHR4A, SCR1–4 and SCR5–8 are highly correlated based on nucleotide and amino acid sequence identity, likely a result of intramolecular duplication. Like all CFHRs, both CFHR4 isoforms lack SCRs homologous to the N-terminal complement repressive domains SCR1–4 of FH and CFHL1. The two C-terminal domains of CFHR4A and CFHR4B are homologous to the C-terminal FH domain SCR19–20, which contains C3b / C3d binding sites. CFHR4B has been shown to bind to the C3d region of C3b via its C-terminal SCR4–5. However, apart from a slight increase in FH cofactor activity in the presence of high CFHR4B concentrations, this C3b binding ability was not associated with any significant function. The interaction between CFHR4A isoforms and C3b and complement regulatory activity has not yet been characterized.

[0050] Age-related macular degeneration (AMD) is a progressive retinal disease characterized in its early stages by a relatively small number of drusen within the macula. As AMD progresses, the size and number of drusen increase, eventually leading to more advanced stages. Advanced AMD presents in two forms. The first is neovascular AMD, characterized by abnormal blood vessels infiltrating the retina. These newly formed vessels are fragile, and once they rupture, blood components leak from the retina, causing sudden vision loss. The second form of advanced AMD is geographic atrophy (GA), caused by the gradual degeneration of the retinal retina (RPE) and photoreceptor cells. Although neovascularization occurs in only 15–20% of AMD cases, it is the vast majority of causes of vision loss in AMD. Drugs targeting vascular endothelial growth factor (VEGF), one of the core molecules in neovascularization, have proven very successful in treating neovascular AMD. However, there are no available treatments for the vast majority of other early, intermediate, or geographic atrophic AMD cases, and no effective means to stop the progression from early to late stages. Although AMD is known to result from a complex interplay of environmental and genetic risk factors, research into the molecular composition of drusen suggests that AMD may have an immunological component. This suggestion was made after proteins (including components of the complement system) associated with inflammation and / or other immune-related responses were discovered in drusen.

[0051] In light of this, experiments were conducted to determine the potential role of CFHR4 in AMD and other etiologies affecting the optic nerve and GA, and simultaneously to develop a therapeutic platform based on modulating CFHR4 activity using anti-CFHR4 antibodies.

[0052] definition

[0053] To facilitate understanding of this technology, several terms and phrases are defined below. Additional definitions are set forth throughout the detailed description.

[0054] Unless otherwise specified herein or obviously contradicted by the context, the use of the terms "a," "an," "the," and "at least one," and similar indicators in the context of describing embodiments of this disclosure (especially in the context of the following claims) shall be interpreted as including both the singular and the plural. Unless otherwise specified herein or obviously contradicted by the context, the use of the term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") shall be interpreted as referring to one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B). Unless otherwise stated, the terms "comprising," "having," "including," and "containing" shall be interpreted as open-ended terms (i.e., meaning "including but not limited to"). Unless otherwise specified herein, references to value ranges herein are intended only as a convenient way of individually referring to individual values ​​within the range, and the individual values ​​are incorporated herein as if they were individually described herein. Unless otherwise specified herein or obviously contradicted by the context, all methods described herein may be performed in any suitable order. Unless otherwise required, the use of any and all instances or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate the various embodiments of this disclosure and does not impose any limitation on the scope of these embodiments. The language in this specification should not be construed as indicating that any unclaimed element is necessary for practicing the various embodiments of this disclosure.

[0055] As used herein, unless the context clearly specifies otherwise, the term “or” is an inclusive “or” operator and is equivalent to the term “and / or”. The term “based on” is not exclusive and allows for basing on other factors not described, unless the context clearly specifies otherwise. Furthermore, throughout the specification, the meanings of “an” and “described” include plural references. The meaning of “in” includes both “in” and “on”.

[0056] The transitional phrase “consistently of…” used in the claims of this application limits the scope of the claims to the specified materials or steps “and those materials or steps that do not substantially affect the basic and novel features of the claimed invention,” as discussed in In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461,463 (CCPA 1976). For example, a composition “consistently of the listed elements” may contain a level of unlisted contaminants such that, although present, the contaminants do not alter the function of the listed composition compared to the pure composition (i.e., a composition “consisting of the listed components”).

[0057] As used herein, the term “one or more” refers to a number greater than one. For example, the term “one or more” covers any of the following: two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, twenty or more, fifty or more, 100 or more, or even a larger number.

[0058] The terms "one or more but less than higher numbers", "two or more but less than higher numbers", "three or more but less than higher numbers", "four or more but less than higher numbers", "five or more but less than higher numbers", "six or more but less than higher numbers", "seven or more but less than higher numbers", "eight or more but less than higher numbers", "nine or more but less than higher numbers", "ten or more but less than higher numbers", "eleven or more but less than higher numbers", "twelve or more but less than higher numbers", "thirteen or more but less than higher numbers", "fourteen or more but less than higher numbers", or "fifteen or more but less than higher numbers" are not limited to higher numbers. For example, the higher number can be 10,000, 1,000, 100, 50, etc. For example, the higher number could be approximately 50 (e.g., 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 32, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2).

[0059] As used herein, the terms "immunoglobulin" or "antibody" refer to proteins found in the blood or other bodily fluids of vertebrates that are used by the immune system to identify and neutralize foreign substances, such as bacteria and viruses. Typically, immunoglobulins or antibodies are proteins containing at least one complementarity-determining region (CDR). The CDR forms the "hypervariate region" of the antibody responsible for antigen binding (discussed further below). A complete antibody typically consists of four polypeptides: two identical copies of the heavy (H) chain polypeptide and two identical copies of the light (L) chain polypeptide. Each heavy chain contains an N-terminal variable (V) terminus. H ) region and three C-terminal constants (C H1 、C H2 and C H3 The light chain contains an N-terminal variable (V) region, and each light chain contains an N-terminal variable (V) region. L ) region and a C-terminal constant (C L The light chains of an antibody can be designated as one of two different types based on the amino acid sequence of their constant domains: kappa (κ) or lambda (λ). In a typical antibody, each light chain is linked to the heavy chain by a disulfide bond, and the two heavy chains are linked to each other by disulfide bonds. The variable regions of the light chains are aligned with the variable regions of the heavy chains, and the constant regions of the light chains are aligned with the first constant region of the heavy chains. The remaining constant regions of the heavy chains are aligned with each other.

[0060] The variable regions of each pair of light and heavy chains form the antigen-binding sites of antibodies. VH and VL The regions have the same overall structure, and each region contains four frame regions (FW or FR). As used herein, the term "frame region" refers to a relatively conserved amino acid sequence located between CDRs within the variable region. Each variable domain has four frame regions, which are designated as FR1, FR2, FR3, and FR4. The frame regions form β-sheets that provide the structural framework of the variable region (see, for example, CA Janeway et al. (eds.), Immunobiology, 5th ed., Garland Publishing, New York, NY (2001)).

[0061] The frame region is linked by three CDRs. As discussed above, the three CDRs (designated CDR1, CDR2, and CDR3) form the “hypervariant region” of the antibody responsible for antigen binding. The CDRs form linking loops and, in some cases, constitute part of the β-sheet structure formed by the frame region. While the constant regions of the light and heavy chains do not directly participate in antibody-antigen binding, they can influence the orientation of the variable region. The constant regions also exhibit various effector functions, such as participating in antibody-dependent complement-mediated cleavage or antibody-dependent cytotoxicity via interactions with effector molecules and cells.

[0062] As used herein, when an antibody or other entity (e.g., an antigen-binding domain) “specifically recognizes” or “specifically binds” to an antigen or epitope, the antibody or other entity preferentially recognizes the antigen in a complex mixture of proteins and / or macromolecules and binds the antigen or epitope with a significantly higher affinity than other entities that do not exhibit the antigen or epitope. In this regard, “significantly higher affinity” means that the affinity is high enough to enable the detection of an antigen or epitope different from the entity using the desired assay or measurement device. Typically, this means a binding affinity of at least 10. 7 M -1 (For example, >10) 7 M -1 >10 8 M -1 >10 9 M -1 >10 10 M -1 >10 11 M -1 >10 12 M -1 >10 13 M -1 The binding constant (K) of (etc.) a In some such implementations, the antibody can bind to different antigens, as long as the different antigens contain the specific epitope. For example, in some cases, homologous proteins from different species may contain the same epitope.

[0063] The terms “fragment of antibody,” “antibody fragment,” and “antigen-binding fragment of antibody” are used interchangeably herein to refer to one or more fragments of an antibody that retain the ability to specifically bind antigens (see generally Holliger et al., Nat. Biotech., 23(9): 1126-1129 (2005)). Any antigen-binding fragment of an antibody described herein is within the scope of this disclosure. Antibody fragments are intended to contain, for example, one or more CDRs, variable regions (or portions thereof), constant regions (or portions thereof), or combinations thereof. Examples of antibody fragments include, but are not limited to: (i) Fab fragments, which are formed by V L 、V H 、C L and C H1 (ii) The F(ab')2 fragment, which is a bivalent fragment consisting of two Fab fragments connected by a disulfide bridge at the hinge region, and (iii) the Fv fragment, which consists of the V of the antibody single arm. L and V HThe domains consist of: (iv) the Fab' fragment, which is formed by breaking the disulfide bridge of the F(ab')2 fragment using mild reducing conditions; (v) the disulfide-stabilized Fv fragment (dsFv); and (vi) the domain antibody (dAb), which is an antibody monovariable domain (V) that specifically binds to the antigen. H or V L Polypeptide.

[0064] As used herein, the term "monoclonal antibody" refers to an antibody produced by a single clone of B lymphocytes that targets a single epitope on an antigen. Monoclonal antibodies are typically produced using hybridoma technology, as first described in Köhler and Milstein, Eur. J. Immunol., 5: 511-519 (1976). Monoclonal antibodies can also be produced using recombinant DNA methods (see, for example, U.S. Patent 4,816,567), isolated from phage display antibody libraries (see, for example, Clackson et al., Nature, 352: 624-628 (1991); and Marks et al., J. Mol. Biol., 222: 581-597 (1991)), or produced by transgenic mice carrying a fully human immunoglobulin system (see, for example, Lonberg, Nat. Biotechnol., 23(9): 1117-25 (2005) and Lonberg, Handb. Exp. Pharmacol., 181: 69-97 (2008)). In contrast, “polyclonal” antibodies are antibodies secreted by different B cell lineages within an animal. Polyclonal antibodies are a collection of immunoglobulin molecules that recognize multiple epitopes on the same antigen.

[0065] The terms “nucleic acid,” “polynucleotide,” “nucleotide sequence,” and “oligonucleotide” are used interchangeably herein and refer to polymers or oligomers of pyrimidine and / or purine bases (preferably cytosine, thymine, and uracil, and adenine and guanine, respectively) (see Albert L. Lehninger, Principles of Biochemistry, pp. 793–800 (Worth Pub. 1982)). The terms encompass any deoxyribonucleotide, ribonucleotide, or peptide nucleic acid component and any chemical variant thereof, such as methylated, hydroxymethylated, or glycosylated forms of these bases. Polymers or oligomers may be heterogeneous or homogeneous in composition, isolated from naturally occurring sources, or produced artificially or synthetically. Furthermore, nucleic acids may be DNA or RNA or mixtures thereof, and may exist permanently or intermittently in single-stranded or double-stranded form (including homoduplexes, heteroduplexes, and hybrid states). In some embodiments, the nucleic acid or nucleic acid sequence comprises other types of nucleic acid structures, such as, for example, DNA / RNA helices, peptide nucleic acids (PNAs), morpholinonucleotides (see, for example, Braasch and Corey, Biochemistry, 41(14): 4503-4510 (2002) and U.S. Patent 5,034,506), locked nucleic acids (LNAs; see Wahllestedt et al., Proc. Natl. Acad. Sci. USA, 97: 5633-5638 (2000)), cyclohexenyl nucleic acids (see Wang, J. Am. Chem. Soc., 122: 8595-8602 (2000)) and / or ribonucleases. The terms “nucleic acid” and “nucleic acid sequence” may also encompass chains comprising non-natural nucleotides, modified nucleotides, and / or non-nucleotide building blocks (e.g., “nucleotide analogs”) that can exhibit the same function as natural nucleotides.

[0066] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein and refer to a polymer of amino acids of any length, which may include coding and non-coding amino acids, chemically or biochemically modified or derived amino acids, and polypeptides having a modified peptide backbone.

[0067] As used herein, “nucleic acid” or “nucleic acid molecule” generally refers to any ribonucleic acid or deoxyribonucleic acid, which may be unmodified or modified DNA or RNA. “Nucleic acid” includes, but is not limited to, single-stranded and double-stranded nucleic acids. As used herein, the term “nucleic acid” also includes DNA containing one or more modified bases as described above. Therefore, DNA whose backbone is modified for stability or other reasons is a “nucleic acid.” As used herein, the term “nucleic acid” encompasses such chemically, enzymatically, or metabolically modified forms of nucleic acids, as well as DNA chemical forms specific to viruses and cells (including, for example, simple and complex cells).

[0068] The terms "oligonucleotide," "polynucleotide," "nucleotide," or "nucleic acid" refer to a molecule having two or more, preferably more than three, and usually more than ten deoxyribonucleotides or ribonucleotides. The exact size will depend on many factors, which in turn depend on the final function or use of the oligonucleotide. Oligonucleotides can be produced by any means, including chemical synthesis, DNA replication, reverse transcription, or combinations thereof. Typical deoxyribonucleotides of DNA are thymine, adenine, cytosine, and guanine. Typical ribonucleotides of RNA are uracil, adenine, cytosine, and guanine.

[0069] The terms "complementarity" and "complementarity" refer to nucleotides (e.g., a single nucleotide) or polynucleotides (e.g., a nucleotide sequence) that are related by base pairing rules. For example, sequence 5'-AGT-3' is complementary to sequence 3'-TCA-5'. Complementarity can be "partial," where only some bases of the nucleic acids match according to base pairing rules. Alternatively, there can be "complete" or "full" complementarity between nucleic acids. The degree of complementarity between nucleic acid chains affects the efficiency and strength of hybridization between nucleic acid chains. This is particularly important in amplification reactions and detection methods that depend on the binding between nucleic acids.

[0070] The term "gene" refers to a nucleic acid (e.g., DNA or RNA) sequence containing the coding sequence necessary for the production of RNA or a polypeptide or its precursor. A functional polypeptide may be encoded by the full-length coding sequence or by any portion of the coding sequence, as long as the desired activity or functional property of the polypeptide (e.g., enzyme activity, ligand binding, signal transduction, etc.) is preserved. When used to refer to a gene, the term "part" refers to a segment of the gene. The size of a segment can range from a few nucleotides to the entire gene sequence minus one nucleotide. Therefore, "nucleotides containing at least a portion of a gene" can include a gene segment or the entire gene.

[0071] The term "gene" also encompasses the coding region of a structural gene and includes sequences adjacent to the coding region at both the 5' and 3' ends, for example, a distance of approximately 1 kb at either end, such that a gene corresponds to the length of full-length mRNA (e.g., containing coding sequences, regulatory sequences, structural sequences, and other sequences). A sequence located at the 5' end of the coding region and present on the mRNA is called a 5' untranslated or untranslated sequence. A sequence located at or downstream of the 3' end of the coding region and present on the mRNA is called a 3' untranslated or 3' untranslated sequence. The term "gene" encompasses both the cDNA and genomic forms of a gene. In some organisms (e.g., eukaryotes), the genomic form or clone of a gene contains coding regions interrupted by non-coding sequences called "introns," "insertion regions," or "insertion sequences." Introns are segments of genes transcribed into nuclear RNA (hnRNA); introns may contain regulatory elements such as enhancers. Introns are removed or "cut out" from nuclear transcripts or primary transcripts; therefore, introns are not present in messenger RNA (mRNA) transcripts. mRNA plays a role in translation, specifying the sequence or order of amino acids in the nascent polypeptide.

[0072] In addition to introns, the genomic form of a gene may also include sequences at the 5' and 3' ends of sequences present on the RNA transcript. These sequences are called "flanking" sequences or regions (these flanking sequences are located at the 5' or 3' end of untranslated sequences present on the mRNA transcript). 5' flanking regions may contain regulatory sequences, such as promoters and enhancers, which control or influence gene transcription. 3' flanking regions may contain sequences that guide transcription termination, post-transcriptional cleavage, and polyadenylation.

[0073] When referring to a gene, the term "wildtype" refers to a gene that has the characteristics of a gene isolated from a naturally occurring source. When referring to a gene product, the term "wildtype" refers to a gene product that has the characteristics of a gene product isolated from a naturally occurring source. When referring to a protein, the term "wildtype" refers to a protein that has the characteristics of a naturally occurring protein. As applied to an object, the term "naturally occurring" refers to the fact that the object can be found in nature. For example, polypeptide or polynucleotide sequences that are isolated from natural sources and have not been intentionally modified by laboratory personnel and are present in organisms (including viruses) are naturally occurring. Wildtype genes are usually the genes or alleles most frequently observed in a population and are therefore arbitrarily designated as the "normal" or "wildtype" form of a gene. In contrast, when referring to a gene or gene product, the terms "modified" or "mutated" refer to a gene or gene product that exhibits modifications in sequence and / or functional properties (e.g., altered characteristics) compared to a wild-type gene or gene product. Note that naturally occurring mutants can be isolated; these are identified by the fact that they have altered characteristics compared to wild-type genes or gene products.

[0074] The term "allele" refers to a variation in a gene; such variation includes, but is not limited to, variants and mutants, polymorphic loci and single nucleotide polymorphic loci, frameshift and splicing mutations. Alleles may be naturally present in a population or may appear in the lifetime of any particular individual within the population.

[0075] Therefore, when used to refer to nucleotide sequences, the terms "variant" and "mutant" refer to nucleic acid sequences that differ from another normally related nucleotide sequence by one or more nucleotides. A "variation" is the difference between two different nucleotide sequences; typically, one sequence is a reference sequence.

[0076] The terms “immunogen” and “antigen” are used interchangeably herein and refer to any molecule, compound, or substance that induces an immune response in an animal (e.g., a mammal). An “immune response” can result in, for example, the production of antibodies and / or the activation of immune effector cells. In the context of this disclosure, an antigen may comprise any subunit, fragment, or epitope of any protein or non-protein (e.g., carbohydrate or lipid) molecule that elicits an immune response in a mammal. The term “epitaxe” refers to an antigenic sequence that is recognized by an antibody or antigen receptor. Epitopes are also referred to in the art as “antigenic determinants.” In some embodiments, an epitope is an antigenic region that an antibody specifically binds to. In some embodiments, an epitope may comprise a chemically active surface group of a molecule, such as an amino acid, a sugar side chain, a phosphoryl group, or a sulfonyl group. In some embodiments, an epitope may have specific three-dimensional structural features (e.g., a “conformational” epitope) and / or specific charge features. An antigen may be a virus, bacteria, parasite, fungus, protozoan, prion, cellular, or extracellular protein or peptide that elicits an immune response in a mammal, preferably resulting in protective immunity.

[0077] As used in this article, "pharmaceuticalally acceptable carrier" refers to a component in a pharmaceutical preparation that is non-toxic to the subject, other than the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, buffer solutions, excipients, stabilizers, or preservatives.

[0078] As used herein, the term "pharmaceutical formulation" generally refers to a class of formulations whose form allows the biological activity of the active ingredient contained therein (e.g., anti-CFHR4 antibody, antibody conjugate, fusion protein, or polymer formulation) to be effective, and which does not contain any other components that would have unacceptable toxicity to the subject to whom the formulation will be administered.

[0079] As used herein, “treatment” (and its grammatical variations, such as “treat” or “treating”) generally refers to a clinical intervention that attempts to alter the natural course of the disease in an individual being treated, and may be performed for prevention or during a clinicopathological process. Desired therapeutic effects include, but are not limited to: preventing the onset or recurrence of disease, relieving symptoms, eliminating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving prognosis. In some embodiments, the anti-CFHR4 antibody of this disclosure or other compositions including the anti-CFHR4 antibody of this disclosure (e.g., antibody conjugates, fusion proteins, or polymer formulations) are used to delay the development of the disease or slow its progression.

[0080] As used herein, the term "half-life" generally refers to the time required for the concentration of a substance (e.g., an anti-CFHR4 antibody, an antibody conjugate, a fusion protein (e.g., a Fab fusion protein), or a polymer formulation) to decrease by half in vivo (e.g., in the eye (e.g., the vitreous humor)) or in vitro.

[0081] The “effective amount” of an agent (e.g., a pharmaceutical preparation) as used herein generally refers to the amount that effectively achieves the desired therapeutic or preventative outcome at the required dosage and time period.

[0082] "Individual" or "subject" is a mammal. Mammals include, but are not limited to: domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates, such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a human. "Subject" can be a "patient".

[0083] Anti-CFHR4 antibody

[0084] As further described herein, embodiments of this disclosure relate to the treatment and / or prevention of age-related macular degeneration (AMD), including advanced forms of dry AMD known as geographic atrophy (GA). Specifically, this disclosure provides novel therapeutic antibodies that target alternative pathway components of the complement activation system, including complement factor H-related (CFHR) 4.

[0085] As further described herein, anti-CFHR4 antibodies were generated, and their structural and functional properties were elucidated. Based on these data, embodiments of this disclosure include anti-CFHR4 antibodies or antigen-binding fragments thereof, said antibodies or antigen-binding fragments thereof comprising a heavy chain variable region (VH) containing complementarity-determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) containing complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3. In some embodiments, HCDR1 comprises one of the following amino acid sequences: (a) X1YX2X3X4 (SEQ ID NO: 1), wherein X1 is S, T, G, or N; X2 is G or Y; X3 is I or M; and X4 is S, H, or Q; (b) X1YX2X3X4 (SEQ ID NO: 21), wherein X1 is S, T, R, or D; X2 is T, V, A, G, S, or E; X3 is M or I; and X4 is N, S, or H; (c) X1X2X3WX4X5 (SEQ ID NO: 53), wherein X1 is T, S, G, or I; X2 is S, R, Y, or H; X3 is D, N, H, K, or Y; X4 is W or S; and X5 is T or S; or (d) SNX1AX2WN (SEQ ID NO: 88), wherein X1 is S, T, or N; and X2 is A or S. In some embodiments, HCDR2 comprises one of the following amino acid sequences: (a) X1X2X3X4X5GX6TX7X8X9X 10 X 11 X 12 QX 13 (SEQ ID NO: 8), wherein X1 is W or I; X2 is S, N or D; X3 is A or P; X4 is Y, N or S; X5 is N, G or S; X6 is N, S or G; X7 is N, H, T or S; X8 is Y or N; X9 is A or Y; X 10 For Q or A; X 11 For K or S; X 12 For L or F; X 13 (a) G or D; (b) X1IX2X3X4X5X6X7X8X9X 10 X 11 DX 12 VX 13 G (SEQ ID NO: 32), wherein X1 is S, V, Y, G, or D; X2 is S or W; X3 is S, V, G, H, or W; X4 is S, D, N, or T; X5 is S or G; X6 is S or G; X7 is Y, S, T, or R; X8 is T, K, I, or V; X9 is Y, F, N, or G; X 10 For Y or H; X 11 For A or V; X 12 For S or P; X 13For R, K, or T; (c)X1X2X3X4X5GX6X7X8X9X 10 PLSX 11 S (SEQ ID NO: 65), wherein X1 is E or Y; X2 is I, T or V; X3 is Y, H or F; X4 is H or Y; X5 is S, D, T, G; X6 is S, T, G or N; X7 is T or I; X8 is N or K; X9 is Y, K or S; X 10 For N, S, K, or H; X 11 For K or Q; or (d) X1TX2YRSX3X4X5X6X7X8X9X 10 SX 11 X 12 S (SEQ ID NO: 102), wherein X1 is R, T, M, or K; X2 is Y or F; X3 is K or R; X4 is W or L; X5 is F, Y, or S; X6 is N, S, D, or A; X7 is N, V, G, D, Y, or A; X8 is Y or F; X9 is S, A, or P; X 10 V, L, or A; X 11 For V or M; X 12 It is K or S. In some embodiments, HCDR3 contains one of the following amino acid sequences: (a) SEQ ID NO: 15-20; (b) SEQ ID NO: 43-52; (c) SEQ ID NO: 77-87; or (d) SEQ ID NO: 116-128.

[0086] In addition to the HCDR1, HCDR2 and HCDR3 sequences described above, the anti-CFHR4 antibody disclosed herein also comprises LCDR1 containing the amino acid sequence of any one of SEQ ID NO: 130-151, SEQ ID NO: 198-199, SEQ ID NO: 207-215 or SEQ ID NO: 237-243; LCDR2 containing the amino acid sequence of any one of SEQ ID NO: 153-174, SEQ ID NO: 201-202, SEQ ID NO: 217-225 or SEQ ID NO: 245-251; and LCDR3 containing the amino acid sequence of any one of SEQ ID NO: 175-196, SEQ ID NO: 204-205, SEQ ID NO: 227-235 or SEQ ID NO: 253-259.

[0087] In some embodiments, this disclosure provides an anti-CFHR4 antibody or an antigen-binding fragment thereof, said antibody or antigen-binding fragment comprising a VH containing complementarity-determining regions HCDR1, HCDR2 and HCDR3, and a VL containing complementarity-determining regions LCDR1, LCDR2 and LCDR3. In some embodiments, LCDR1 comprises one of the following amino acid sequences: (a) RX1SX2X3X4X5X6X7LX8 (SEQ ID NO: 129), wherein X1 is A or T; X2 is Q or K; X3 is G, S, D or N; X4 is I, F or V; X5 is T, R, A, S, N, G or I; X6 is T, N, G, S, I, K or Y; X7 is W, D or Y; X8 is A, T, G, N or D; (b) RSSQX1LLHSX2GYNX3LD (SEQ ID NO: 197), wherein X1 is S or R; X2 is T or S; X3 is F or Y; (c) RASQX1X2X3X4X5X6X7X8A (SEQ ID NO: 197) 206), wherein X1 is S, N or T; X2 is V or I; X3 is S or R; X4 is S, G or N; X5 is N or S; X6 is L or Y; X7 is A, L or V; or (d) SEQ ID NO: 236. In some embodiments, LCDR2 comprises one of the following amino acid sequences: (a) X1X2SX3LX4X5 (SEQ ID NO: 152), wherein X1 is G, A, T, or K; X2 is A or T; X3 is S, T, G, or N; X4 is E, Q, or L; and X5 is S, T, or G; (b) LX1SX2RAS (SEQ ID NO: 200), wherein X1 is A or G; and X2 is N or S; (c) GASX1RAT (SEQ ID NO: 216), wherein X1 is T, S, or N; or (d) WASX1RES (SEQ ID NO: 244), wherein X1 is T, P, or N. In some embodiments, LCDR3 comprises one of the following amino acid sequences: (a) SEQ ID NO: 175-196; (b) MQX1LQTPX2T (SEQ ID NO: 203), wherein X1 is A or G; X2 is Y or P; (c) QX1YX2X3X4X5X6T (SEQ ID NO: 226), wherein X1 is Q or H; X2 is D or G; X3 is N, S or R; X4 is W or S; X5 is R, P, F, Y, V or I; X6 is T, W, L or I; or (d) QQX1X2X3X4PX5X6T (SEQ ID NO: 252), wherein X1 is Y or F; X2 is G or Y; X3 is S or N; X4 is S, T or I; X5 is M, Y or R; X6 is Y or T.

[0088] In addition to the LCDR1, LCDR2, and LCDR3 sequences described above, the anti-CFHR4 antibody disclosed herein also comprises HCDR1 containing the amino acid sequence of any one of SEQ ID NO: 2-7, SEQ ID NO: 22-31, SEQ ID NO: 54-64, or SEQ ID NO: 89-101; HCDR2 containing the amino acid sequence of any one of SEQ ID NO: 9-14, SEQ ID NO: 33-42, SEQ ID NO: 66-76, or SEQ ID NO: 103-115; and HCDR3 containing the amino acid sequence of any one of SEQ ID NO: 15-20, SEQ ID NO: 43-52, SEQ ID NO: 77-87, or SEQ ID NO: 116-128.

[0089] In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 2, HCDR2 of SEQ ID NO: 9, and HCDR3 of SEQ ID NO: 15. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 3, HCDR2 of SEQ ID NO: 10, and HCDR3 of SEQ ID NO: 16. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 11, and HCDR3 of SEQ ID NO: 17. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 5, HCDR2 of SEQ ID NO: 12, and HCDR3 of SEQ ID NO: 18. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 13, and HCDR3 of SEQ ID NO: 19. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 7, HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and HCDR3 comprising SEQ ID NO: 20. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 22, HCDR2 comprising the amino acid sequence of SEQ ID NO: 33, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 43. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 34, and HCDR3 of SEQ ID NO: 44. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 35, and HCDR3 of SEQ ID NO: 45. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 25, HCDR2 of SEQ ID NO: 36, and HCDR3 of SEQ ID NO: 46. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 26, HCDR2 of SEQ ID NO: 37, and HCDR3 of SEQ ID NO: 47. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 27, HCDR2 of SEQ ID NO: 38, and HCDR3 of SEQ ID NO: 48.In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 28, HCDR2 of SEQ ID NO: 39, and HCDR3 of SEQ ID NO: 49. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 29, HCDR2 of SEQ ID NO: 40, and HCDR3 of SEQ ID NO: 50. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 30, HCDR2 of SEQ ID NO: 41, and HCDR3 of SEQ ID NO: 51. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 31, HCDR2 of SEQ ID NO: 42, and HCDR3 of SEQ ID NO: 52. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 54, HCDR2 of SEQ ID NO: 66, and HCDR3 of SEQ ID NO: 77. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 55, HCDR2 of SEQ ID NO: 67, and HCDR3 of SEQ ID NO: 78. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 56, HCDR2 of SEQ ID NO: 68, and HCDR3 of SEQ ID NO: 79. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 57, HCDR2 of SEQ ID NO: 69, and HCDR3 of SEQ ID NO: 80. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 58, HCDR2 of SEQ ID NO: 70, and HCDR3 of SEQ ID NO: 81. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 59, HCDR2 of SEQ ID NO: 71, and HCDR3 of SEQ ID NO: 82. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 60, HCDR2 of SEQ ID NO: 72, and HCDR3 of SEQ ID NO: 83. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 61, HCDR2 of SEQ ID NO: 73, and HCDR3 of SEQ ID NO: 84.In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 62, HCDR2 of SEQ ID NO: 74, and HCDR3 of SEQ ID NO: 85. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 63, HCDR2 of SEQ ID NO: 75, and HCDR3 of SEQ ID NO: 86. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 64, HCDR2 of SEQ ID NO: 76, and HCDR3 of SEQ ID NO: 87. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 89, HCDR2 of SEQ ID NO: 103, and HCDR3 of SEQ ID NO: 116. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 90, HCDR2 of SEQ ID NO: 104, and HCDR3 of SEQ ID NO: 117. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 91, HCDR2 of SEQ ID NO: 105, and HCDR3 of SEQ ID NO: 118. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 92, HCDR2 of SEQ ID NO: 106, and HCDR3 of SEQ ID NO: 119. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 93, HCDR2 of SEQ ID NO: 107, and HCDR3 of SEQ ID NO: 120. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 94, HCDR2 of SEQ ID NO: 108, and HCDR3 of SEQ ID NO: 121. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 95, HCDR2 of SEQ ID NO: 109, and HCDR3 of SEQ ID NO: 122. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 96, HCDR2 of SEQ ID NO: 110, and HCDR3 of SEQ ID NO: 123. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 97, HCDR2 of SEQ ID NO: 111, and HCDR3 of SEQ ID NO: 124.In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 98, HCDR2 of SEQ ID NO: 112, and HCDR3 of SEQ ID NO: 125. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 99, HCDR2 of SEQ ID NO: 113, and HCDR3 of SEQ ID NO: 126. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 100, HCDR2 of SEQ ID NO: 114, and HCDR3 of SEQ ID NO: 127. In some embodiments, the anti-CFHR4 antibody comprises HCDR1 of SEQ ID NO: 101, HCDR2 of SEQ ID NO: 115, and HCDR3 of SEQ ID NO: 128.

[0090] In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 130, LCDR2 of SEQ ID NO: 153, and LCDR3 of SEQ ID NO: 175. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 131, LCDR2 of SEQ ID NO: 154, and LCDR3 of SEQ ID NO: 176. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 132, LCDR2 of SEQ ID NO: 155, and LCDR3 of SEQ ID NO: 177. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 133, LCDR2 of SEQ ID NO: 156, and LCDR3 of SEQ ID NO: 178. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 134, LCDR2 of SEQ ID NO: 157, and LCDR3 of SEQ ID NO: 179. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 135, LCDR2 of SEQ ID NO: 158, and LCDR3 of SEQ ID NO: 180. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 136, LCDR2 of SEQ ID NO: 159, and LCDR3 of SEQ ID NO: 181. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 137, LCDR2 of SEQ ID NO: 160, and LCDR3 of SEQ ID NO: 182. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 138, LCDR2 of SEQ ID NO: 161, and LCDR3 of SEQ ID NO: 183. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 139, LCDR2 of SEQ ID NO: 162, and LCDR3 of SEQ ID NO: 184. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 140, LCDR2 of SEQ ID NO: 163, and LCDR3 of SEQ ID NO: 185. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 141, LCDR2 of SEQ ID NO: 164, and LCDR3 of SEQ ID NO: 186.In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 142, LCDR2 of SEQ ID NO: 165, and LCDR3 of SEQ ID NO: 187. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 143, LCDR2 of SEQ ID NO: 166, and LCDR3 of SEQ ID NO: 188. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 144, LCDR2 of SEQ ID NO: 167, and LCDR3 of SEQ ID NO: 189. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 145, LCDR2 of SEQ ID NO: 168, and LCDR3 of SEQ ID NO: 190. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 146, LCDR2 of SEQ ID NO: 169, and LCDR3 of SEQ ID NO: 191. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 147, LCDR2 of SEQ ID NO: 170, and LCDR3 of SEQ ID NO: 192. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 148, LCDR2 of SEQ ID NO: 171, and LCDR3 of SEQ ID NO: 193. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 149, LCDR2 of SEQ ID NO: 172, and LCDR3 of SEQ ID NO: 194. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 150, LCDR2 of SEQ ID NO: 173, and LCDR3 of SEQ ID NO: 195. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 151, LCDR2 of SEQ ID NO: 174, and LCDR3 of SEQ ID NO: 196. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 198, LCDR2 of SEQ ID NO: 201, and LCDR3 of SEQ ID NO: 204. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 199, LCDR2 of SEQ ID NO: 202, and LCDR3 of SEQ ID NO: 205.In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 207, LCDR2 of SEQ ID NO: 217, and LCDR3 of SEQ ID NO: 227. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 208, LCDR2 of SEQ ID NO: 218, and LCDR3 of SEQ ID NO: 228. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 209, LCDR2 of SEQ ID NO: 219, and LCDR3 of SEQ ID NO: 229. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 210, LCDR2 of SEQ ID NO: 220, and LCDR3 of SEQ ID NO: 230. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 211, LCDR2 of SEQ ID NO: 221, and LCDR3 of SEQ ID NO: 231. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 212, LCDR2 of SEQ ID NO: 222, and LCDR3 of SEQ ID NO: 232. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 213, LCDR2 of SEQ ID NO: 223, and LCDR3 of SEQ ID NO: 233. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 214, LCDR2 of SEQ ID NO: 224, and LCDR3 of SEQ ID NO: 234. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 215, LCDR2 of SEQ ID NO: 225, and LCDR3 of SEQ ID NO: 235. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 237, LCDR2 of SEQ ID NO: 245, and LCDR3 of SEQ ID NO: 253. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 238, LCDR2 of SEQ ID NO: 246, and LCDR3 of SEQ ID NO: 254. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 239, LCDR2 of SEQ ID NO: 247, and LCDR3 of SEQ ID NO: 255.In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 240, LCDR2 of SEQ ID NO: 248, and LCDR3 of SEQ ID NO: 256. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 241, LCDR2 of SEQ ID NO: 249, and LCDR3 of SEQ ID NO: 257. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 242, LCDR2 of SEQ ID NO: 250, and LCDR3 of SEQ ID NO: 258. In some embodiments, the anti-CFHR4 antibody comprises LCDR1 of SEQ ID NO: 243, LCDR2 comprising SEQ ID NO: 251, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 259.

[0091] In some embodiments, the VH of the anti-CFHR4 antibody of this disclosure comprises an amino acid sequence having at least 90% identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity) with any of the following: (a) SEQ ID NO: 260-265; (b) SEQ ID NO: 284-293; (c) SEQ ID NO: 324-334; or (d) SEQ ID NO: 368-380. In some embodiments, the VL of the anti-CFHR4 antibody of this disclosure comprises an amino acid sequence having at least 90% identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity) with any of the following: (a) SEQ ID NO: 272-277; (b) SEQ ID NO: 304-313; (c) SEQ ID NO: 346-356; or (d) SEQ ID NO: 394-406.

[0092] In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 260 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 272 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 261 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 273 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 262 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 274 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 263 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 275 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity).In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 264 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 276 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 265 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 277 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 284 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 304 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 285 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 305 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity).In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 286 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 306 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 287 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 307 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 288 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 308 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 289 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 309 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity).In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 290 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 310 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 291 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 311 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 292 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 312 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 293 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 313 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity).In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 324 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 346 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 325 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 347 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 326 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 348 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 327 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 349 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity).In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 328 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 350 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 329 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 351 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 330 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 352 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 331 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 353 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity).In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 332 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 354 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 333 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 354 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 334 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 356 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 368 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 394 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity).In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 369 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 395 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 370 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 396 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence having at least 90% identity with SEQ ID NO: 371 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence having at least 90% identity with SEQ ID NO: 397 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 372 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 398 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity).In some embodiments, VH contains an amino acid sequence having at least 90% identity with SEQ ID NO: 373 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence having at least 90% identity with SEQ ID NO: 399 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 374 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 400 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 375 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 401 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 376 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 402 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity).In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 377 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 403 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 378 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 404 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 379 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 405 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity). In some embodiments, VH contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 380 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity), and VL contains an amino acid sequence that has at least 90% identity with SEQ ID NO: 406 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity).

[0093] As described herein, the “identity” of a nucleic acid or amino acid sequence can be determined by comparing the nucleic acid or amino acid sequence of interest with a reference nucleic acid or amino acid sequence. Many mathematical algorithms for obtaining optimal alignments and calculating the identity between two or more sequences are known and incorporated into numerous available software programs. Examples of such programs include CLUSTAL-W, T-Coffee, and ALIGN (for nucleic acid and amino acid sequence alignment), BLAST programs (e.g., BLAST 2.1, BL2SEQ, and subsequent versions), and FASTA programs (e.g., FASTA3x, FAS™, and SSEARCH) (for sequence alignment and sequence similarity searches). Sequence alignment algorithms are also disclosed in, for example, Altschul et al., J.Molecular Biol., 215(3): 403-410 (1990); Beigert et al., Proc. Natl. Acad. Sci.USA, 106(10): 3770-3775 (2009); Durbin et al. (ed.), Biological Sequence Analysis: Probabilistic Models of Proteins and Nucleic Acids, Cambridge University Press, Cambridge, UK (2009); Soding, Bioinformatics, 21(7): 951-960 (2005); Altschul et al., Nucleic Acids Res., 25(17): 3389-3402 (1997); and Gusfield, Algorithms on Strings, Trees and Sequences, Cambridge University Press, Cambridge UK (1997)).

[0094] As those skilled in the art will recognize based on this disclosure, one or more amino acids in the aforementioned anti-CFHR4 antibody or its antigen fragment may be replaced or substituted with different amino acids. An amino acid "replacement" or "substitution" means that one amino acid at a given position or residue within a polypeptide sequence is replaced by another amino acid at the same position or residue. Amino acids are broadly classified as "aromatic" or "aliphatic." Aromatic amino acids include aromatic rings. Examples of "aromatic" amino acids include histidine (H or His), phenylalanine (F or Phe), tyrosine (Y or Tyr), and tryptophan (W or Trp). Non-aromatic amino acids are broadly classified as "aliphatic." Examples of aliphatic amino acids include glycine (G or Gly), alanine (A or Ala), valine (V or Val), leucine (L or Leu), isoleucine (I or Ile), methionine (M or Met), serine (S or Ser), threonine (T or Thr), cysteine ​​(C or Cys), proline (P or Pro), glutamic acid (E or Glu), aspartic acid (A or Asp), asparagine (N or Asn), glutamine (Q or Gln), lysine (K or Lys), and arginine (R or Arg). Aliphatic amino acids can be further subdivided into four subgroups. The "large aliphatic nonpolar subgroup" consists of valine, leucine, and isoleucine. The "aliphatic weakly polar subgroup" consists of methionine, serine, threonine, and cysteine. The "aliphatic polar / charged subgroup" consists of glutamic acid, aspartic acid, asparagine, glutamine, lysine, and arginine. The "small residue subgroup" consists of glycine and alanine. The charged / polar amino acid group can be further subdivided into three subgroups: the "positively charged subgroup" composed of lysine and arginine, the "negatively charged subgroup" composed of glutamic acid and aspartic acid, and the "polar subgroup" composed of asparagine and glutamine. Aromatic amino acids can be further subdivided into two subgroups: the "nitrogen-cyclic subgroup" composed of histidine and tryptophan, and the "phenyl subgroup" composed of phenylalanine and tyrosine.

[0095] Amino acid substitutions or replacements can be conserved, semi-conserved, or non-conserved. The phrase "conservative amino acid substitution" or "conservative mutation" refers to the replacement of one amino acid with another that shares a common characteristic. One functional way to define the common characteristic between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (Principles of Protein Structure, Springer-Verlag, New York (1979)). Based on such analysis, amino acid groups can be defined where amino acids within a group preferentially exchange with each other, thus having the most similar effects on the overall protein structure. Examples of conserved amino acid substitutions include amino acid substitutions within the aforementioned subgroups, such as lysine replacing arginine and vice versa, to maintain a positive charge; glutamic acid replacing aspartic acid and vice versa, to maintain a negative charge; serine replacing threonine, to maintain a free -OH group; and glutamine replacing asparagine, to maintain a free -NH2 group. "Semi-conservative mutations" include amino acid substitutions within the same group but not within the same subgroup as listed above. For example, substitutions such as aspartic acid replacing asparagine or asparagine replacing lysine involve amino acids from the same group but different subgroups. "Non-conservative mutations" involve amino acid substitutions between different groups (e.g., lysine replacing tryptophan or phenylalanine replacing serine, etc.).

[0096] Additionally, one or more amino acids may be inserted into the anti-CFHR4 antibody or its antigen-binding fragment (e.g., into the amino acid sequence of the heavy chain and / or light chain variable region). Any number of suitable amino acids may be inserted into the amino acid sequence of the antibody or its antigen-binding fragment. In this regard, at least one amino acid (e.g., two or more, five or more, or ten or more amino acids) but no more than 20 amino acids (e.g., 18 or fewer, 15 or fewer, or 12 or fewer amino acids) may be inserted into the amino acid sequence of the antibody or its antigen-binding fragment. For example, one to ten amino acids (e.g., one, two, three, four, five, six, seven, eight, nine, or ten amino acids) may be inserted into the amino acid sequence of the monoclonal antibody or its antigen-binding fragment. In this regard, amino acids may be inserted at any suitable position on the antibody or its antigen-binding fragment. Preferably, the amino acid is inserted into the CDR (e.g., CDR1, CDR2, or CDR3) of the antibody or its antigen-binding fragment.

[0097] The amino acid sequence of an anti-CFHR4 antibody or its antigen-binding fragment is not limited to the specific amino acid sequence described herein. In fact, an anti-CFHR4 antibody or its antigen-binding fragment may comprise any heavy-chain or light-chain polypeptide that competes with the anti-CFHR4 antibody or its antigen-binding fragment for conformational binding of CFHR4. Antibody competition can be determined using conventional peptide competition assays, such as, for example, ELISA, Western blotting, or immunohistochemical methods (see, for example, U.S. Patents 4,828,981 and 8,568,992; and Braitbard et al., Proteome Sci., 4: 12 (2006)).

[0098] The anti-CFHR4 antibody disclosed herein may be a complete antibody or an antigen-binding fragment of a complete antibody. As defined herein, the antigen-binding antibody fragments covered herein include, but are not limited to: F(ab')2, Fab', Fab, Fv, scFv, dsFv, dAb, and single-chain binding peptides. Antibody fragments and their therapeutic efficacy are further described, for example, in Nelson, AL, MAbs. Jan-Feb 2010; 2(1): 77-83; Joosten et al., Microbial Cell Factories Vol. 2, Article No. 1 (2003); and Bates A, Power CA., Antibodies (Basel). 2019;8(2):28; doi:10.3390 / antib8020028). In some embodiments, the anti-CFHR4 antigen-binding fragment is a single-chain variable fragment (scFv) engineered antibody generated by fusing the heavy chain (VH) and light chain (VL) of an immunoglobulin through a short peptide linker. Single-chain variable domain (Fv) fragments (scFv) are used in the field for a variety of clinical and therapeutic applications, primarily because they offer improved pharmacokinetic properties compared to parental monoclonal antibodies and are relatively easy to mass-produce at low cost (Monnier et al., Antibodies 2013, 2(2), 193-208; doi.org / 10.3390 / antib2020193; Safdari et al., Mol Med. 2016; 22: 258-270; and Lu, R., Hwang, Y., Liu, I. et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 27, 1 (2020). https: / / doi.org / 10.1186 / s12929-019-0592-z).

[0099] The anti-CFHR4 antibody disclosed herein may be a biantibody. A biantibody is an antibody fragment that may be bivalent or bispecific and has two antigen-binding sites. See, for example, EP 404,097; WO 1993 / 01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Tri- and tetra-antibodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003). The anti-CFHR4 antibody disclosed herein may also be a single-domain antibody (also known as a nanobody). A single-domain antibody is an antibody fragment containing all or part of the variable domain of the heavy chain or all or part of the variable domain of the light chain. In some embodiments, the single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.; see, for example, U.S. Patent No. 6,248,516 B1). Antibody fragments can be prepared using a variety of techniques, including but not limited to proteolytic digestion of intact antibodies as described herein and production from recombinant host cells (e.g., E. coli or bacteriophages).

[0100] In other embodiments, the anti-CFHR4 antibody is a complete antibody. As defined herein, a complete antibody comprises two identical copies of the heavy (H) chain polypeptide and two identical copies of the light (L) chain polypeptide. Each heavy chain contains an N-terminal variable (V) terminus. H ) region and three C-terminal constants (C H1 、C H2 and C H3 The light chain contains an N-terminal variable (V) region, and each light chain contains an N-terminal variable (V) region. L ) region and a C-terminal constant (C LThe C-terminal constant region of the heavy chain contains a fragment crystallizable (Fc) domain, which determines the antibody class and is responsible for humoral and cellular effector functions. Antibodies are classified into five major classes (or “isotypes”): IgG, IgM, IgA, IgD, and IgE, which have different functions in the immune system. IgG is the most abundant immunoglobulin in the blood, accounting for 60% of total antibodies in human serum. IgG antibodies can be further subdivided into IgG1, IgG2, IgG3, and IgG4, named in order of their abundance in serum (IgG1 is the most abundant) (Vidarsson et al., Frontiers in Immunology. 5: 520 (2014)). The complete anti-CFHR4 monoclonal antibody described herein may belong to any suitable class and / or subclass. In some embodiments, the monoclonal antibody belongs to the IgG class (e.g., IgG1, IgG2, IgG3, or IgG4). For example, the monoclonal antibody may be an IgG1 antibody.

[0101] As discussed above, the Fc domain mediates several effector functions of antibodies, such as binding to receptors on target cells and complement fixation (which triggers the elimination of antigens). In some embodiments, the Fc domain can be modified or engineered to alter its effector function. For example, the Fc domain can be modified to enhance antibody-dependent cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADCP) and to control serum half-life. In some embodiments, the Fc domain of an anti-CFHR4 antibody can be engineered to modulate affinity for Fc receptors such as the Fcγ receptor (FcγR) and the neonatal Fc receptor (FcRn). In fact, optimizing the interaction between antibodies and FcγR has become a promising approach for enhancing the activity of therapeutic antibodies in treating various diseases (Mimoto et al., Curr. Pharm. Biotechnol. 17, 1298-1314 (2016); Lazar et al., Proc. Natl Acad. Sci. USA 103, 4005-4010 (2006); Richards et al., Mol. Cancer Ther. 7, 2517-2527 (2008); Nordstrom et al., Breast Cancer Res.13, R123 (2011); and Kang, TH, Jung, ST, Exp Mol Med 51, 1-9 (2019)). The Fc domain can also be modified to improve serum half-life, for example, by engineering IgG Fc to obtain higher FcRn binding (Zalevsky et al., Nat. Biotechnol. 28, 157-159 (2010); and Dall'Acqua et al., J. Immunol. 169, 5171-5180 (2002)). In other embodiments, the Fc domain can be modified to produce monovalent or antibody bispecificity, thereby improving therapeutic efficacy. For example, an Fc domain mFc that does not form a homodimer but remains a soluble monomer can be generated, which exhibits high affinity for FcγRI but has no detectable binding to FcγRIIIa. In other embodiments, a heterodimeric Fc domain can be generated to obtain bispecific antigen binding properties, thereby avoiding the formation of homodimers.Engineered Fc domains can be generated by inducing point mutations or by modifying the glycosylation of the Fc domain (Saunders, KO, Front Immunol. 2019;10:1296; Kelley, RF, Meng, YG, Liu et al., J Biol Chem. 2014;289:3571-90; Monnet et al., MAbs. 2014;6:422-36; Li et al., Proc Natl Acad Sci US A. 2017;114:3485-90; and Lin et al., Proc Natl Acad Sci US A. 2015;112:10611-6; Kang and Jung, ibid.).

[0102] Multispecific anti-CFHR4 antibody

[0103] As described above, the anti-CFHR4 antibody of this disclosure can be a monoclonal antibody, a human antibody, a humanized antibody, and / or a chimeric antibody. In some embodiments, the antibody is a fragment selected from the group consisting of: Fab, Fab-C, Fab′-SH, Fv, scFv, and (Fab′)2 fragments. In some embodiments, the anti-CFHR4 antibody is a monospecific antibody. In some embodiments, the anti-CFHR4 antibody is a bispecific antibody. In some embodiments, the anti-CFHR4 antibody comprises two or more single-domain antibodies, said single-domain antibodies forming bivalent, trivalent, or quadrivalent antibodies that recognize different epitopes on the same or different antigens.

[0104] In some embodiments, the anti-CFHR4 antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA. 81:6851-6855 (1984). In one instance, the chimeric antibody comprises a non-human variable region (e.g., a variable domain derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant domain. In a further instance, the chimeric antibody is a “class-switched” antibody, wherein the class or subclass has been changed from that of the parent antibody. The chimeric antibody includes its antigen-binding fragment.

[0105] In some embodiments, the chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce its immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Typically, a humanized antibody contains one or more variable domains in which the HVR, such as the CDR (or a portion thereof), is derived from the non-human antibody, and the FR (or a portion thereof) is derived from the human antibody sequence. The humanized antibody may optionally also contain at least a portion of a human constant region. In some embodiments, some FR residues in the humanized antibody are substituted with corresponding residues from the non-human antibody (e.g., an antibody derived from HVR residues) to, for example, restore or enhance antibody specificity or affinity.

[0106] Humanized antibodies and their preparation methods are reviewed, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008) and further described, for example, in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); US Patent Nos. 5,821,337, 7,527,791, 6,982,321 and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity-determining region (SDR) transplantation); Padlan, Mol. Immunol. 28:489-498 (1991) (describing “resurfacing”); Dall'Acqua et al., Methods 36:43-60 (2005) (describes “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br.J. Cancer, 83:252-260 (2000) (describes the “guided selection” method for FR shuffling).

[0107] According to the above embodiments, the anti-CFHR4 antibody of this disclosure can be prepared in bivalent, trivalent, or tetravalent form. For example, the anti-CFHR4 antibody of this disclosure can be a bivalent, bispecific antibody with a heterologous heavy chain (e.g., Triomab, knobs-into-holes (KIH), Duobody, etc.). The anti-CFHR4 antibody disclosed herein can be a tetravalent multispecific antibody composed of IgG and other binding domains fused to the N-terminus or C-terminus of the heavy or light chain (e.g., dual variable domain [DVD], IgG-scFv fusion, Mabtyrin (IgG, wherein a non-antibody binding scaffold "centyrin" is fused to the C-terminus of the heavy chain). The anti-CFHR4 antibody of this disclosure can also be composed of IgG with additional antigen-binding sites added to its structure (e.g., a two-in-one antibody, F-Star's MAT "modular antibody technology" platform). The anti-CFHR4 antibody of this disclosure can be an engineered antibody fragment linked by a short peptide linker, which can be prepared in a bivalent, trivalent, or tetravalent form targeting two to three targets (e.g., a bispecific T-cell adaptor (BiTE), a nanobody platform, a dual-affinity retargeting (DART) antibody, a "tandem antibody" structure (TandAbs)). Furthermore, the anti-CFHR4 antibody of this disclosure can be composed of chemically conjugated IgG.

[0108] In some embodiments, the anti-CFHR4 antibody of this disclosure is a multispecific antibody, such as a bispecific antibody, which has binding specificity to at least two different antigens. In some embodiments, the anti-CFHR4 antibody of this disclosure or its antigen-binding fragment can be used to form one arm (e.g., the antigen-binding portion) of a bispecific antibody, while the other arm of the bispecific antibody may be specific to a different antigen. In some embodiments, other antigens include, but are not limited to: interleukin-1β (IL-1β), interleukin-6 (IL-6); interleukin-6 receptor (IL-6R); interleukin-13 (IL-13); IL-13 receptor (IL-13R); PDGF (e.g., PDGF-BB); angiopoietin; angiopoietin 2. (Ang2); Tie2; S1P; integrins αvβ3, αvβ5 and α5β1; betacellulin; apelin / APJ; erythropoietin; complement factor D; TNFα; HtrA1; VEGF receptors (e.g., VEGFR1, VEGFR2, VEGFR3, membrane-bound VEGF receptor (mbVEGFR) or soluble VEGF receptor (sVEGFR)); ST-2 receptor; and proteins genetically associated with age-related macular degeneration (AMD) risk, such as complement pathway components C2, factor B, factor H, CFHR3, C3b, C5, C5a and C3a; HtrA1; ARMS2; TIMP3; HLA; interleukin-8 (IL-8); CX3CR1; TLR3; TLR4; CETP; LIPC; COL10A1; and TNFRSF10A.In other embodiments, the bispecific antibody may have binding specificity to the following: CFHR4 and IL-1β; CFHR4 and IL-6; CFHR4 and IL-6R; CFHR4 and IL-13; CFHR4 and IL-13R; CFHR4 and PDGF (e.g., PDGF-BB); CFHR4 and angiopoietin; CFHR4 and Ang2; CFHR4 and Tie2; CFHR4 and S1P; CFHR4 and integrin αvβ3; CFHR4 and integrin αvβ5; CFHR4 and integrin α5β1; CFHR4 and betacellulin; CFHR4 and apelin / APJ; CFHR4 and erythropoietin; CFHR4 and complement factor D; CFHR4 and TNFα; CFHR4 and HtrA1; CFHR4 and VEGF receptors (e.g., VEGFR1, VEGFR2, VEGFR3, mbVEG). FR or sVEGFR); CFHR4 and ST-2 receptors; CFHR4 and C2; CFHR4 and factor B; CFHR4 and factor H; CFHR4 and CFHR3; CFHR4 and C3b; CFHR4 and C5; CFHR4 and C5a; CFHR4 and C3a; CFHR4 and ARMS2; CFHR4 and TIMP3; CFHR4 and HLA; CFHR4 and IL-8; CFHR4 and CX3CR1; CFHR4 and TLR3; CFHR4 and TLR4; CFHR4 and CETP; CFHR4 and LIPC; CFHR4 and COL10A1; or CFHR4 and TNFRSF10A.

[0109] In some embodiments, the bispecific antibodies of this disclosure comprise an anti-CFHR4 antibody or an antigen-binding fragment thereof and an anti-VEGF antibody or an antigen-binding fragment thereof. Such bispecific antibodies can be used to target complement activation pathways from two different mechanisms, and thus provide additional therapeutic benefits. For example, the anti-CFHR4 arm can be any anti-CFHR4 antibody disclosed herein, and the anti-VEGF arm can be any VEGF antagonist, including but not limited to anti-VEGF antibodies (e.g., bevacizumab, sevacizumab, and ranibizumab), anti-VEGFR2 antibodies and related molecules (e.g., ramucirumab, tanibirumab, and aflibercept), anti-VEGFR1 antibodies and related molecules (e.g., icrucumab, aflibercept (VEGF Trap-Eye; EYLEA®), and ziv-aflibercept (VEGF Trap; ZALTRAP®), and anti-VEGF arms of VEGF bispecific antibodies (e.g., MP-0250, vanucizumab (VEGF-ANG2)), including anti-VEGF, anti-VEGFR1, and anti-VEGFR2 arms.

[0110] In other embodiments, the bispecific antibodies of this disclosure comprise an anti-CFHR4 antibody or an antigen-binding fragment thereof and an anti-C3 antibody or an antigen-binding fragment thereof. Such bispecific antibodies can be used to target complement activation pathways from two different mechanisms and thus provide additional therapeutic benefits. For example, the anti-CFHR4 arm can be any anti-CFHR4 antibody of this disclosure, and the anti-C3 arm can be any C3 antagonist, including but not limited to POT-4 (AL-78898A), APL-2, and NGM621.

[0111] In other embodiments, the bispecific antibody of this disclosure comprises an anti-CFHR4 antibody or an antigen-binding fragment thereof and an anti-C5 antibody or an antigen-binding fragment thereof. For example, the anti-CFHR4 arm can be any anti-CFHR4 antibody of this disclosure, and the anti-C5 arm can be any C5 antagonist, including but not limited to eculizumab and tesidolumab (LFG316). In other embodiments, the bispecific antibody of this disclosure comprises an anti-CFHR4 antibody or an antigen-binding fragment thereof and an anti-FD antibody or an antigen-binding fragment thereof. For example, the anti-CFHR4 arm can be any anti-CFHR4 antibody of this disclosure, and the anti-C5 arm can be any C5 antagonist, including but not limited to lambalizumab.

[0112] Functional characteristics of anti-CFHR4 antibodies

[0113] According to the above embodiments, this disclosure provides anti-CFHR4 antibodies comprising various functional features. In some embodiments, the anti-CFHR4 antibodies described herein bind to the antigen or a variant or isoform of CFHR4 (SEQ ID NO: 580) (via interaction with its antigenic determinant (epitope). In some embodiments, binding of the anti-CFHR4 antibody to CFHR4 reduces complement activation. In some embodiments, the anti-CFHR4 antibody is present at about 100 nM or less. KD Combined with human CFHR4b ( Figure 6 ).

[0114] In some embodiments, the antibody cross-reacts with the cynomolgus monkey CFHR4b protein (cCFHR4b). In some embodiments, the antibody comprises VH and VL regions having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-560, ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-569, ATX-P-570, ATX-P-571, and ATX-P-572. 3. ATX-P-574, ATX-P-576, ATX-P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX- P-583, ATX-P-587, ATX-P-588, ATX-P-591, ATX-P-592, ATX-P-594, ATX-P-596, ATX-P-600 and ATX-P-604( Figure 7 ).

[0115] In some embodiments, the antibody does not cross-react with the cynomolgus monkey CFHR4b protein (cCFHR4b). In some embodiments, the antibody comprises VH and VL regions having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-572, ATX-P-595, ATX-P-597, ATX-P-598, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-607, ATX-P-608, ATX-P-609, and ATX-P-610 (…). Figure 7 ).

[0116] In some embodiments, the antibody cross-reacts with complement factor H-related protein 4a (CFHR4a). In some embodiments, the antibody comprises VH and VL regions having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-560, ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-569, ATX-P-570, ATX-P-571, ATX-P-572, ATX-P-573, ATX-P-574, ATX-P-576, ATX-P-577, and ATX-P-577. 8. ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX-P-583, ATX-P-587, ATX-P-588, ATX-P-591, ATX-P-592, ATX-P-594, ATX-P-59 5. ATX-P-596, ATX-P-597, ATX-P-600, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-604, ATX-P-607, ATX-P-608, ATX-P-609 and ATX-P-610 ( Figure 8 ).

[0117] In some embodiments, the antibody does not cross-react with complement factor H-related protein 4a (CFHR4a). In some embodiments, the antibody comprises a VH region and a VL region having at least 90% identity with ATX-P-598. Figure 8 ).

[0118] In some embodiments, the antibody cross-reacts with complement factor H-related protein 3 (CFHR3). In some embodiments, the antibody comprises a VH region and a VL region having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-569, ATX-P-572, ATX-P-573, ATX-P-574, ATX-P-576, ATX... -P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-583, ATX-P-587, ATX-P-588, ATX-P-592, A TX-P-594, ATX-P-595, ATX-P-596, ATX-P-600, ATX-P-603, ATX-P-604, ATX-P-608, ATX-P-609 and ATX-P-610 ( Figure 9 ).

[0119] In some embodiments, the antibody does not cross-react with complement factor H-related protein 3 (CFHR3). In some embodiments, the antibody comprises a VH region and a VL region having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-560, ATX-P-570, ATX-P-571, ATX-P-582, ATX-P-591, ATX-P-597, ATX-P-598, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-604, and ATX-P-607 (…). Figure 9 ).

[0120] In some embodiments, the antibody cross-reacts with complement factor H-related protein 1 (CFHL1). In some embodiments, the antibody comprises a VH and VL region having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-570, ATX-P-571, ATX-P-573, and ATX-P-574. 4. ATX-P-576, ATX-P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX-P-58 3. ATX-P-587, ATX-P-588, ATX-P-591, ATX-P-594, ATX-P-595, ATX-P-596, ATX-P-600 and ATX-P-604 ( Figure 10 ).

[0121] In some embodiments, the antibody does not cross-react with complement factor H-related protein 1 (CFHL1). In some embodiments, the antibody comprises a VH region and a VL region having at least 90% identity with the VH and VL regions of antibodies selected from the group consisting of: ATX-P-560, ATX-P-569, ATX-P-572, ATX-P-592, ATX-P-597, ATX-P-598, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-607, ATX-P-608, ATX-P-609, and ATX-P-610 (…). Figure 10 ).

[0122] Embodiments of this disclosure also include means for evaluating one or more functional and / or biochemical characteristics of the anti-CFHR4 antibody described herein. In one embodiment, this disclosure provides a C3 convertase assembly assay (… Figures 11A to 11C The C3 convertase assembly assay was developed as an antibody screening assay to evaluate the ability of the CFHR4 antibody disclosed herein to affect C3 convertase formation. Figure 11AMore specifically, C3bBb is a C3 convertase of the complement activation alternative pathway (EC 3.4.21.43). The C3 enzyme is responsible for activation of the amplification pathway and deposition of the C3b and membrane attack complex on target cells. It is controlled by serum protein factors H and I (EC 3.4.21.45) and serum sterilizing proteins. The formation of C3 convertase requires C3b, factor B, factor D (EC 3.4.21.46), and Mg2+. After the formation of the reversible bimolecular complex C3bB(Mg), factor D cleaves factor B, releasing the activating fragment Ba, and generating the active enzyme C3bBb. The C3 enzyme is a serine protease with its catalytic site located in the Bb subunit. Furthermore, CFHR4 has been reported to directly promote the formation of C3 convertase by binding to C3b, exhibits a stronger ability to assemble C3bBb on CFHR4, and the C3bBb-CFHR4 complex is more resistant to CFH cleavage compared to C3bBb.

[0123] Therefore, the C3 convertase assay of this disclosure aims to test the ability of CHFR4 antibodies to disrupt the formation of the C3 convertase complex by measuring the amount of factor B present using an anti-FB monoclonal antibody conjugated to the reporter portion. Figure 11A As illustrated, in the presence of CFHR4 (but without an effective CFHR4 antibody), a C3 convertase complex is formed, and the anti-FB antibody binds to FB and a signal is detected (i.e., complement activation). However, in the presence of an effective anti-CFHR4 antibody, the C3 convertase complex is disrupted, and the antibody-bound FB is washed away, resulting in a weakened signal (i.e., no complement activation).

[0124] like Figure 11B As shown, dose-response curves were generated for the top 8 inhibitory antibodies screened in the C3 convertase assembly assay. The percentage of C3 convertase activity relative to the negative control (diluted only) was plotted. Figure 11C Including targeting Figure 11BThe IC50 value was calculated for each antibody tested. Therefore, based on these assay results, certain anti-CFHR4 antibodies of this disclosure attenuate C3 convertase activity. In some embodiments, the VH of the anti-CFHR4 antibody contains an amino acid sequence having at least 90% identity with SEQ ID NO: 330, and the VL contains an amino acid sequence having at least 90% identity with SEQ ID NO: 352. In some embodiments, the VH of the anti-CFHR4 antibody contains an amino acid sequence having at least 90% identity with SEQ ID NO: 293, and the VL contains an amino acid sequence having at least 90% identity with SEQ ID NO: 313. In some embodiments, the VH of the anti-CFHR4 antibody contains an amino acid sequence having at least 90% identity with SEQ ID NO: 378, and the VL contains an amino acid sequence having at least 90% identity with SEQ ID NO: 404. In some embodiments, the VH of the anti-CFHR4 antibody contains an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 377, and the VL contains an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 403. In some embodiments, the VH of the anti-CFHR4 antibody contains an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 376, and the VL contains an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 402. In some embodiments, the VH of the anti-CFHR4 antibody contains an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 289, and the VL contains an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 309. In some embodiments, the VH of the anti-CFHR4 antibody contains an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 371, and the VL contains an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 397. In some embodiments, the VH of the anti-CFHR4 antibody contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 284, and the VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 304. Figures 11A to 11C ).

[0125] peptides and expression vectors

[0126] Embodiments of this disclosure also include a polynucleotide encoding any anti-CFHR4 antibody of this disclosure. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 381-393. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 380-393. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419.

[0127] In some embodiments, the polynucleotide comprises a sequence having at least 75% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 381-393. In some embodiments, the polynucleotide comprises a sequence having at least 75% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419. In some embodiments, the polynucleotide comprises a sequence having at least 75% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 380-393. In some embodiments, the polynucleotide comprises a sequence having at least 75% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419.

[0128] In some embodiments, the polynucleotide comprises a sequence having at least 80% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 381-393. In some embodiments, the polynucleotide comprises a sequence having at least 80% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419. In some embodiments, the polynucleotide comprises a sequence having at least 80% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 380-393. In some embodiments, the polynucleotide comprises a sequence having at least 80% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419.

[0129] In some embodiments, the polynucleotide comprises a sequence having at least 85% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 381-393. In some embodiments, the polynucleotide comprises a sequence having at least 85% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419. In some embodiments, the polynucleotide comprises a sequence having at least 85% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 380-393. In some embodiments, the polynucleotide comprises a sequence having at least 85% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419.

[0130] In some embodiments, the polynucleotide comprises a sequence having at least 90% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 381-393. In some embodiments, the polynucleotide comprises a sequence having at least 90% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419. In some embodiments, the polynucleotide comprises a sequence having at least 90% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 380-393. In some embodiments, the polynucleotide comprises a sequence having at least 90% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419.

[0131] In some embodiments, the polynucleotide comprises a sequence having at least 95% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 381-393. In some embodiments, the polynucleotide comprises a sequence having at least 95% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419. In some embodiments, the polynucleotide comprises a sequence having at least 95% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NO: 335-345; or (d) SEQ ID NO: 380-393. In some embodiments, the polynucleotide comprises a sequence having at least 95% identity with any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NO: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NO: 407-419.

[0132] In some embodiments, the polynucleotide encoding the anti-CFHR4 antibody of this disclosure comprises: (a) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 266, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 278; and (b) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 279. A nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (c) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 269, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 280; (d) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 279, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 280 ... 281. A nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (e) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 270, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 282;Or (f) a nucleic acid sequence having at least 70% identity with SEQ ID NO:270 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity), and a nucleic acid sequence having at least 70% identity with SEQ ID NO:283 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity).

[0133] In some embodiments, the polynucleotide encoding the anti-CFHR4 antibody of this disclosure comprises: (a) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 294, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 314; and (b) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 315. A nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (c) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 296, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 316; (d) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 297, and ... 317 A nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (e) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 298, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 318;(f) Nucleic acid sequences having at least 70% identity with SEQ ID NO:299 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity), and nucleic acid sequences having at least 70% identity with SEQ ID NO:319 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (g) Nucleic acid sequences having at least 70% identity with SEQ ID NO:300 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity), and nucleic acid sequences having at least 70% identity with SEQ ID NO:320 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (h) Nucleic acid sequences having at least 70% identity with SEQ ID NO:300 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); The following nucleic acid sequences are described: (i) a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 301; (i) a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 321; or (j) a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 302; or (j) a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 322; or (j) a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 301. The nucleic acid sequence NO:303 has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO:323, and the nucleic acid sequence has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO:323.

[0134] In some embodiments, the polynucleotide encoding the anti-CFHR4 antibody of this disclosure comprises: (a) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 335, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 357; and (b) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: (c) A nucleic acid sequence having at least 70% identity with SEQ ID NO: 338 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 358 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity), and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 359 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 338 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity), and a nucleic acid sequence having at least 70% identity with SEQ ID NO: 35 ... 360 has a nucleic acid sequence with at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (e) a nucleic acid sequence with at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 339, and a nucleic acid sequence with at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 361;(f) Nucleic acid sequences having at least 70% identity with SEQ ID NO:340 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity), and nucleic acid sequences having at least 70% identity with SEQ ID NO:362 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (g) Nucleic acid sequences having at least 70% identity with SEQ ID NO:341 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity), and nucleic acid sequences having at least 70% identity with SEQ ID NO:363 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (h) Nucleic acid sequences having at least 70% identity with SEQ ID NO:340 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); The following nucleic acid sequences are described: (i) a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 342; (j) a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 364; (i) a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 342; and (j) a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 365; and (j) a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 342; The nucleic acid sequence NO:344 has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO:366; or (k) the nucleic acid sequence has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO:345; and the nucleic acid sequence has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO:367.

[0135] In some embodiments, the polynucleotide encoding the anti-CFHR4 antibody of this disclosure comprises: (a) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 381, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 407; and (b) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: (c) A nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 383, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 409; (d) A nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 384, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 389. 410 A nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (e) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 385, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 411;(f) Nucleic acid sequences having at least 70% identity with SEQ ID NO:386 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity), and nucleic acid sequences having at least 70% identity with SEQ ID NO:412 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (g) Nucleic acid sequences having at least 70% identity with SEQ ID NO:387 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity), and nucleic acid sequences having at least 70% identity with SEQ ID NO:413 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (h) Nucleic acid sequences having at least 70% identity with SEQ ID NO:386 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); The following nucleic acid sequences are described: (i) NO:388 having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (j) SEQ ID NO:414 having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (i) SEQ ID NO:389 having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); and (j) SEQ ID NO:415 having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); (k) A nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 390, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 416; (k) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 391, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) with SEQ ID NO: 417;(l) a nucleic acid sequence having at least 70% identity with SEQ ID NO:392 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity), and a nucleic acid sequence having at least 70% identity with SEQ ID NO:418 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity); or (m) a nucleic acid sequence having at least 70% identity with SEQ ID NO:393 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity), and a nucleic acid sequence having at least 70% identity with SEQ ID NO:419 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity).

[0136] According to these embodiments, this disclosure includes an expression vector comprising any polynucleotide encoding an anti-CFHR4 antibody of this disclosure. In some embodiments, the expression vector is adapted to manufacture the anti-CFHR4 antibody of this disclosure for delivery to a subject. In some embodiments, the nucleic acid sequence is in the form of a vector. The vector may be, for example, a plasmid, episome, granulosome, viral vector (e.g., retrovirus or adenovirus) or phage. Suitable vectors and methods of vector preparation are well known in the art (see, for example, Sambrook et al., Molecular Cloning, a Laboratory Manual, 4th edition, Cold Spring Harbor Press, Cold Spring Harbor, NY (2012), and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, NY (1994)).

[0137] In addition to the nucleic acid encoding an anti-CFHR4 antibody or its antigen-binding fragment, the vector desiccates to contain expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), etc., to provide expression of the antibody-encoded nucleic acid sequence in the host cell. Exemplary expression control sequences are known in the art and described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, Calif. (1990).

[0138] Vectors containing nucleic acid sequences encoding anti-CFHR4 antibodies or their antigen-binding fragments can be introduced into host cells capable of expressing their encoded polypeptides, including any suitable prokaryotic or eukaryotic cells. Examples of suitable prokaryotic cells include, but are not limited to, cells of the genera *Bacillus* (such as *Bacillus subtilis* and *Bacillus brevis*), *Escherichia* (such as *E. coli*), *Pseudomonas*, *Streptomyces*, *Salmonella*, and *Erwinia*. Particularly useful prokaryotic cells include various strains of *Escherichia coli* (e.g., K12, HB101 (ATCC No. 33694), DH5α, DH10, MC1061 (ATCC No. 53338), and CC102). Suitable eukaryotic cells are known in the art and include, for example, yeast cells, insect cells, and mammalian cells. Examples of suitable yeast cells include cells of *Hansenula*, *Kluyveromyces*, *Pichia*, *Rhinosporidium*, *Saccharomyces*, and *Schizosaccharomyces*. Suitable insect cells include Sf-9 cells and HIS cells (Invitrogen, Carlsbad, Calif.) and are described, for example, in Kitts et al., *Biotechniques*, 14: 810-817 (1993); Lucklow, *Curr. Opin. Biotechnol.*, 4: 564-572 (1993); and Lucklow et al., *J. Virol.*, 67: 4566-4579 (1993). Examples of suitable mammalian cell lines include, but are not limited to: Chinese hamster ovary cells (CHO) (ATCC designation CCL61), CHO DHFR cells (Urlaub et al., Proc. Natl. Acad. Sci. USA, 97: 4216-4220 (1980)), human embryonic peptide kidney (HEK) 293 cells or 293T cells (ATCC designation CRL1573), and 3T3 cells (ATCC designation CCL92). Other suitable mammalian cell lines are the monkey COS-1 cell line (ATCC designation CRL1650) and COS-7 cell line (ATCC designation CRL1651), as well as the CV-1 cell line (ATCC designation CCL70).Further exemplary mammalian host cells include primate and rodent cell lines, including transformed cell lines. Normal diploid cells, cell lines derived from primary tissue culture in vitro, and primary explants are also suitable. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa cells, mouse L-929 cells, and BHK or HaK hamster cell lines, all of which are available from ATCC. Methods for selecting suitable mammalian host cells and for transforming, culturing, expanding, screening, and purifying such cells are well known in the art (see, for example, Ausubel et al., eds., Short Protocols in Molecular Biology, 5th ed., John Wiley & Sons, Inc., Hoboken, NJ (2002)). Preferably, the mammalian cells are human cells.

[0139] In some embodiments, the vector may include a manner for ligating the detection portion to the anti-CFHR4 antibody of this disclosure. In some embodiments, the vector may include a manner for ligating the purified portion to the anti-CFHR4 antibody of this disclosure. Exemplary detection and / or purified portions / tags that may be conjugated to the anti-CFHR4 antibody of this disclosure include, but are not limited to: hemagglutinin (HA), c-Myc, V5, DYKDDDDK, His tag (e.g., 6x-HIS), glutathione S-transferase (GST), maltose-binding protein (MBP), fluorophores (e.g., green fluorescent protein (GFP), red fluorescent protein (RFP), mCherry), chromophores, and / or luminescent peptides (e.g., luciferase).

[0140] In some embodiments, the expression vector is suitable for gene therapy (e.g., an expression vector for delivering a polynucleotide encoding an anti-CFHR4 antibody disclosed herein to a subject). In some embodiments, the expression vector is a herpes simplex virus (HSV) vector or a retroviral vector. In some embodiments, the expression vector is an adeno-associated virus (AAV) vector or contains an AAV backbone. For example, AAV vectors have been designed, manufactured, and used to mediate gene delivery to human subjects, including for therapeutic purposes. Typically, AAV vectors used for gene transfer contain a replication-deficient AAV genome that lacks functional Rep and Cap encoding viral sequences. Such replication-deficient AAV vectors more preferably lack most or all of the Rep and Cap encoding sequences and substantially retain one or two AAV ITR sequences and packaging sequences. The defective genome is packaged in viral particles to form a defective recombinant AAV virus, also referred to as an "AAV vector". Methods for producing such AAV vectors have been disclosed in the literature, including the use of packaging cells, helper viruses or plasmids and / or baculovirus systems (Samulski et al., (1989) J. Virology 63, 3822; Xiao et al., (1998) J. Virology 72, 2224; Inoue et al., (1998) J. Virol. 72, 7024; WO98 / 22607; WO2005 / 072364). Methods for producing pseudotyped AAV vectors have also been reported (e.g., WO00 / 28004), as well as various modifications or formulations of AAV vectors that reduce their immunogenicity when administered in vivo (see, for example, WO001 / 23001; WO00 / 73316; WO04 / 112727; WO005 / 005610; WO99 / 06562). AAV vectors can be prepared from or derived from various serotypes of AAV, and can even be mixed together or with other types of viruses to produce chimeric (e.g., pseudotyped) AAV viruses. Examples of tAAVs are human AAV4 vectors, human AAV7 vectors, human AAV9 vectors, human AAV10 vectors, or bovine AAV vectors. AAV vectors can be derived from a single AAV serotype or contain sequences or components derived from at least two different AAV serotypes (pseudotyped AAV vectors), for example, an AAV vector containing an AAV genome derived from one AAV serotype (e.g., AAV9) and a capsid at least partially derived from different AAV serotypes. As used herein, an AAV vector is a vector containing at least one component that can be derived from adeno-associated virus. Preferably, this component is involved in the biological mechanism of vector infection or transduction of target cells and expression of the anti-CFHR4 antibody of this disclosure (e.g., ocular delivery / expression).

[0141] In other implementations, the expression vector is a lentiviral vector (LV) or contains an LV backbone. Lentivirals are part of a large class of retroviruses. A detailed list of lentiviruses can be found in Coffin et al. (1997) “Retroviruses”, Cold Spring Harbour Laboratory Press, eds. JM Coffin, SM Hughes, HE Varmus, pp. 758-763. For example, lentiviruses can be divided into primate and non-primate groups. Examples of primate lentiviruses include, but are not limited to, human immunodeficiency virus (HIV), the pathogen of human autoimmune syndrome (AIDS), and simian immunodeficiency virus (SIV). The non-primate lentivirus group includes the prototype “slow virus” visna / maedi virus (VMV), and related caprine arthritis-encephalitis virus (CAEV), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), maedi-visna virus (MVV), and bovine immunodeficiency virus (BIV). In one embodiment, the lentiviral vector is derived from HIV-1, HIV-2, SIV, FIV, BIV, EIAV, CAEV, or Vesna lentivirus. The lentiviral family differs from retroviruses in that lentiviruses can infect both dividing and non-dividing cells (Lewis et al. (1992) EMBO J 11 (8): 3053-3058 and Lewis and Emerman (1994) J Virol 68 (1): 510-516). In contrast, other retroviruses, such as MLV, cannot infect non-dividing or slowly dividing cells, such as those constituting tissues like muscle, brain, lung, and liver. As used herein, a lentiviral vector is a vector containing at least one component that may be derived from a lentivirus. Preferably, this component is involved in the biological mechanisms by which the vector infects or transduces target cells and expresses the anti-CFHR4 antibody of this disclosure (e.g., ocular delivery / expression).

[0142] Other compositions and methods for ocular gene therapy can be found, for example, Bordet, T. and Behar-Cohen, F., “Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives,” Drug Discovery Today, Vol. 24, No. 8, August 2019, pp. 1685-1693. In some embodiments, gene therapy platforms, methods, and compositions that can be used to deliver the anti-CFHR4 antibody of this disclosure to a subject (e.g., ocular delivery) include those disclosed in US20220025396, US20220011308, US20210371877, US20210363192, US20190078099, US20190038724, and US10494646B2, which are incorporated herein by reference. In other embodiments, gene therapy platforms, methods, and compositions that can be used to deliver the anti-CFHR4 antibody of this disclosure to a subject (e.g., ocular delivery) include HMR59-based platforms, methods, and compositions, which block the membrane attack complex formed during the terminal step of the complement cascade via their protein product, soluble CD59. HMR59 is designed for administration via a single intraocular injection.

[0143] According to these embodiments, this disclosure also provides a method of administering ocular gene therapy to a subject in need, the method comprising injecting a pharmaceutical composition comprising an effective amount of the expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-CFHR4 antibody of this disclosure). As further described below, this disclosure also provides a method of treating AMD and / or GA, the method comprising administering a pharmaceutical composition comprising an effective amount of the expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-CFHR4 antibody of this disclosure). In some embodiments, administering the pharmaceutical composition treats at least one AMD symptom and / or GA.

[0144] Compositions and methods of treatment

[0145] The anti-CFHR4 antibody disclosed herein can be administered as part of a pharmaceutical composition in a therapeutically effective amount to treat an ocular disease (e.g., AMD or GA). In some embodiments, the composition is suitable for ocular administration. In some embodiments, ocular administration includes injection into the vitreous fluid. In some embodiments, ocular administration includes delivery of the antibody using conjunctival inserts, contact lenses, gels, nanoparticles, mucosal adhesion polymers, ointments, solutions, suspensions, eye drops, and / or implants (e.g., Susvimo™). Recent methods and formulations for ocular administration can be found, for example, in Souto, EB et al., “Advanced Formulation Approaches for Ocular Drug Delivery: State-Of-The-Art and Recent Patents,” Pharmaceutics, Sep 2019; 11(9): 460).

[0146] According to these embodiments, the method includes administering a pharmaceutical composition comprising a therapeutically effective amount of the anti-CFHR4 antibody of this disclosure. In some embodiments, the pharmaceutical composition is administered ocularly and treats at least one AMD symptom. In some embodiments, AMD includes wet AMD. In some embodiments, AMD includes dry AMD (e.g., GA). In some embodiments, at least one AMD symptom includes visual distortion, decreased central vision, blurred vision, and / or difficulty adapting to low light. In some embodiments, administering the pharmaceutical composition reduces complement activation in the subject's eye.

[0147] In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of the antiCFHR4 antibody of this disclosure is administered at a dose ranging from about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 0.001 mg / dose to about 100 mg / dose. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 0.01 mg / dose to about 100 mg / dose. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 0.1 mg / dose to about 100 mg / dose. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 1.0 mg / dose to about 100 mg / dose. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 10 mg / dose to about 100 mg / dose. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 0.0001 mg / dose to about 10 mg / dose. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.0001 mg / dose to about 1.0 mg / dose. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.0001 mg / dose to about 0.1 mg / dose. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.0001 mg / dose to about 0.001 mg / dose. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.01 mg / dose to about 10 mg / dose. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.001 mg / dose to about 1.0 mg / dose. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.1 mg / dose to about 10 mg / dose.

[0148] In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of the antiCFHR4 antibody of this disclosure is administered at a dose ranging from about 0.0001 mg / ml to about 100 mg / ml. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 0.001 mg / ml to about 100 mg / ml. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 0.01 mg / ml to about 100 mg / ml. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 0.1 mg / ml to about 100 mg / ml. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 1.0 mg / ml to about 100 mg / ml. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 10 mg / ml to about 100 mg / ml. In some embodiments, the antiCFHR4 antibody is administered at a dose ranging from about 0.0001 mg / ml to about 10 mg / ml. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.0001 mg / ml to about 1.0 mg / ml. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.0001 mg / ml to about 0.1 mg / ml. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.0001 mg / ml to about 0.01 mg / ml. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.0001 mg / ml to about 0.001 mg / ml. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.01 mg / ml to about 10 mg / ml. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.001 mg / ml to about 1.0 mg / ml. In some embodiments, the anti-CFHR4 antibody is administered at a dose ranging from about 0.1 mg / ml to about 10 mg / ml.

[0149] As used herein, the terms “treatment,” “treating,” etc., refer to achieving a desired pharmacological and / or physiological effect. In some embodiments, the effect is therapeutic, meaning that the effect partially or completely cures the disease and / or adverse symptoms attributable to the disease. To this end, the methods of this disclosure include administering a “therapeuticly effective amount” of an antiCFHR4 antibody or a composition containing an antiCFHR4 antibody. A “therapeuticly effective amount” refers to an amount that effectively achieves the desired therapeutic outcome at the necessary dose and time period. Therapeuticly effective amounts can vary depending on factors such as an individual’s disease state, age, sex, and weight, and the ability of the monoclonal antibody to elicit a desired response in the individual. For example, a therapeutically effective amount of the antiCFHR4 antibody of this disclosure is an amount that treats at least one symptom of AMD and / or GA in a subject. In some embodiments, the pharmacological and / or physiological effect may be prophylactic, meaning that the effect completely or partially prevents the disease or its symptoms. In this regard, the methods of this disclosure include administering a “prophylacticly effective amount” of an antiCFHR4 antibody or a composition containing an antiCFHR4 antibody. "Preventive effective dose" refers to the amount that effectively achieves the desired preventive outcome (e.g., prevention of AMD and / or GA) at the required dose and time period.

[0150] Typical therapeutically effective doses of the disclosed anti-CFHR4 antibody for each eye to be treated range from, for example, about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, the therapeutically effective doses of the disclosed anti-CFHR4 antibody range from about 0.001 mg / dose to about 100 mg / dose, about 0.01 mg / dose to about 100 mg / dose, about 0.05 mg / dose to about 50 mg / dose, about 0.1 mg / dose to about 10 mg / dose, about 0.5 mg / dose to about 5 mg / dose, and about 1 mg / dose to about 10 mg / dose. In some embodiments, the therapeutically effective concentrations of the disclosed anti-CFHR4 antibody range from, for example, about 0.0001 mg to about 100 mg antibody per milliliter of solution. In some embodiments, the therapeutically effective concentration of the anti-CFHR4 antibody disclosed herein may range from about 0.001 mg / ml to about 100 mg / ml, about 0.01 mg / ml to about 100 mg / ml, about 0.1 mg / ml to about 100 mg / ml, about 1.0 mg / ml to about 100 mg / ml, about 0.001 mg / ml to about 50 mg / ml, about 0.01 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 25 mg / ml, about 0.1 mg / ml to about 10 mg / ml, and about 1.0 mg / ml to about 10 mg / ml. In some embodiments, the therapeutically effective dose of the anti-CFHR4 antibody of this disclosure may be precisely or approximately 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, or 25.0 mg, or may fall within the range defined by any two of the foregoing values.For example, in some embodiments, the sustained-release formulation (e.g., ocular implant) may be precisely or approximately 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, or 25.0 mg of antiCFHR4 antibody, or an amount falling within the range defined by any two of the foregoing values.

[0151] Therapeutic or prophylactic efficacy can be monitored by periodic evaluation of treated patients. For repeated administration over several days or longer, treatment is repeated as needed until the desired suppression of disease symptoms occurs. However, other dosing regimens may also be useful and are within the scope of this disclosure. The desired dose can be delivered by a single bolus injection, by multiple bolus injections, or by continuous infusion. Compositions containing anti-CFHR4 antibodies or their antigen-binding fragments can be administered to mammals using standard administration techniques, including ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, skin, intramuscular, intranasal, buccal, sublingual, or suppository administration. The composition is preferably suited for ocular administration.

[0152] According to the compositions and treatment methods described herein, embodiments of this disclosure include an anti-CFHR4 antibody having an enhanced half-life (e.g., after ocular application), allowing for administration of the anti-CFHR4 antibody to a subject at a lower frequency. In some embodiments, the antibody comprises a half-life-extending portion. In some embodiments, the half-life-extending portion comprises a polypeptide that can be conjugated to the anti-CFHR4 antibody of this disclosure by any means known in the art (e.g., fusion protein generation). In some embodiments, the polypeptide conjugable to the anti-CFHR4 antibody of this disclosure is at least 20 amino acids in length and comprises any combination of G, A, ST, E, and P residues. In some embodiments, the half-life-extending polypeptide is linked to the C-terminus or N-terminus of the antibody. In some implementations, this is referred to as “XTENylation”, as further described in US8933197, US7846445, US7855279, US8492530, US9938331, US8673860, US9371369, US9926351, US10961287, US10172953 and US10953073.

[0153] This disclosure also provides compositions comprising any of the anti-CFHR4 antibodies or antigen-binding fragments thereof described herein. The compositions are preferably pharmaceutically acceptable (e.g., physiologically acceptable) compositions comprising a carrier, preferably a pharmaceutically acceptable (e.g., physiologically acceptable) carrier, and an anti-CFHR4 antibody or antigen-binding fragment thereof. Any suitable carrier may be used in the context of this disclosure, and such carriers are well known in the art. For example, the compositions may contain preservatives such as, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. A mixture of two or more preservatives may optionally be used. Additionally, the compositions may contain buffers. Suitable buffers include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. A mixture of two or more buffers may optionally be used. Methods for preparing compositions for pharmaceutical use are known to those skilled in the art and described, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st edition (May 1, 2005).

[0154] Once administered to mammals (e.g., humans), the biological activity of an anti-CFHR4 antibody or its antigen-binding fragment can be measured by any suitable method known in the art. For example, biological activity can be assessed by determining the stability of the anti-CFHR4 antibody. The biological activity of an anti-CFHR4 antibody can also be assessed by determining its binding affinity to the CFHR4 peptide and / or by evaluating its binding affinity to peptides that may cross-react with it. The term "affinity" refers to the equilibrium constant for the reversible binding of two agents and is expressed as a dissociation constant (…). KD The affinity of the binder for the ligand, such as the affinity of the antibody for the epitope, can be, for example, from about 1 femtomolar (fM) to about 1 millimole (mM) (e.g., from about 1 picomolar (pM) to about 1 nanomolar (nM) or from about 1 nM to about 1 micromolar (μM)). In some embodiments, the affinity of the anti-CFHR4 antibody can be from about 1 nm to about 20 nm, and preferably from about 5 nm to about 10 nm. The affinity of the antibody for the antigen or epitope of interest can be measured using any assay recognized in the art. Such methods include, for example, fluorescence-activated cell sorting (FACS), separable beads (e.g., magnetic beads), antigen panning, and / or ELISA (see, for example, Janeway et al. (eds.), Immunobiology, 5th edition, Garland Publishing, New York, NY, 2001).

[0155] In some embodiments, the anti-CFHR4 antibody or a composition containing an anti-CFHR4 antibody may be administered alone or in combination with other drugs. For example, the anti-CFHR4 antibody may be administered in combination with other agents disclosed herein for the treatment or prevention of AMD and / or GA. For example, the anti-CFHR4 antibody of this disclosure or its antibody conjugates, fusion proteins, or polymer formulations may be used alone or in combination with other agents in a therapy. For example, the anti-CFHR4 antibody may be co-administered with at least one other therapeutic agent. In some embodiments, the other therapeutic agent is another antibody, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an immunosuppressant, a prodrug, a cytokine, a cytokine antagonist, cytotoxic radiotherapy, a corticosteroid, an antiemetic, a cancer vaccine, an analgesic, a growth inhibitor, or a combination thereof.

[0156] For example, in some embodiments, any of the foregoing methods further includes the administration of one or more other compounds. In some embodiments, the anti-CFHR4 antibody, antibody conjugate, fusion protein, or polymer formulation is administered simultaneously with other compounds. In some embodiments, the anti-CFHR4 antibody, antibody conjugate, fusion protein, or polymer formulation is administered before or after other compounds. In some embodiments, other compounds bind to a second biomolecule selected from the group consisting of: VEGF, IL-1β; IL-6; IL-6R; IL-13; IL-13R; PDGF; angiopoietin; Ang2; Tie2; S1P; integrin αvβ3, αvβ5, and α5β1; β-cytokinin; apralin / APJ; erythropoietin; complement factor D; TNFα; HtrA1; VEGF receptor; ST-2 receptor; and proteins associated with genetic risk of AMD, such as complement pathway components C2, factor B, factor H, CFHR3, C3b, C5, C5a, and C3a; HtrA1; ARMS2; TIMP3; HLA; interleukin-8 (IL-8); CX3CR1; TLR3; TLR4; CETP; LIPC; COL10A1; and TNFRSF10A. In some embodiments, other compounds are antibodies or antigen-binding fragments thereof. In some embodiments according to (or applied to) any of the above embodiments, the ocular condition is an intraocular neovascular disease selected from the following: proliferative retinopathy, choroidal neovascularization (CNV), age-related macular degeneration (AMD), geographic atrophy (GA), diabetic and other ischemic retinopathy, diabetic macular edema, pathological myopia, von Hippel-Lindau disease, ocular histoplasmosis, retinal vein occlusion (RVO), including CRVO and BRVO, corneal neovascularization, retinal neovascularization, and retinopathy of prematurity (ROP).

[0157] In some cases, the anti-CFHR4 antibody or its antibody conjugate, fusion protein, and / or polymer formulation disclosed herein may be administered in combination with at least one other therapeutic agent to treat ocular conditions, such as those described herein (e.g., AMD (e.g., wet AMD or dry AMD), GA, DME, DR, or RVO). Exemplary other therapeutic agents for combination therapies for treating ocular conditions include, but are not limited to, anti-angiogenic agents, such as VEGF antagonists, including, for example, anti-VEGF antibodies (e.g., anti-VEGF Fab LUCENTIS® (ranibizumab)), soluble receptor fusion proteins (e.g., recombinant soluble receptor fusion protein EYLEA® (aflibercept, also known as VEGF Trap Eye; Regeneron / Aventis)), and aptamers (e.g., anti-VEGF pegylated aptamer MACUGEN® (pegaptanib sodium; NeXstarPharmaceuticals / OSI). Pharmaceuticals) and VEGFR tyrosine kinase inhibitors (e.g., 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474)), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidine-1-ylpropoxy)quinazoline (AZD2171), vatalanib (PTK787), smannib (SU5416; SUGEN), and SUTENT® (sunitinib); tryptophanyl-tRNA synthetase (TrpRS); squalamine; RETAANE® (anecortave acetate for sustained-release suspension; Alcon, Inc.); Combretastatin A4 prodrugs (CA4P); MIFEPREX® (mifepristone-ru486); subcapsular triamcinolone acetonide; intravitreal crystalline triamcinolone acetonide; matrix metalloproteinase inhibitors (e.g., promazine stat (AG3340; Pfizer)); fluocinolone acetonide (including fluocinolone intraocular implants; Bausch & Lomb / Control Delivery Systems); linomide; integrin β3 function inhibitors; angiogenesis inhibitors and combinations thereof.

[0158] Other examples of other therapeutic agents that can be used in combination with the anti-CFHR4 antibody or its antibody conjugates, fusion proteins and / or polymer formulations disclosed herein to treat ocular conditions (e.g., AMD, GA, DME, DR or RVO) include, but are not limited to, VISUDYNE® (verteporfin; a photoactivated drug that is typically used in combination with photodynamic therapy using non-thermal lasers), PKC412, Endovion (NS 3728; NeuroSearch A / S), neurotrophic factors (e.g., glial-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF)), diltiazem, dazolamide, PHOTOTROP®, 9-cis-retinaldehyde, ophthalmic drops (e.g., phospholineiodide, echotiophate or carbonic anhydrase inhibitors), vevorstat (AE-941; AETerna Laboratories, Inc.), Sirna-027 (AGF-745; Sirna Therapeutics, Inc.), neurotrophic factors (including, by way of example only, NT-4 / 5, Genentech), Cand5 (Acuity Pharmaceuticals), INS-37217 (Inspire Pharmaceuticals), integrin antagonists (including those from Jerini AG and Abbott Laboratories), EG-3306 (Ark Therapeutics Ltd.), BDM-E (BioDiemLtd.), thalidomide (e.g., EntreMed, Inc.).The following ingredients were used: Cardiac Nutrient-1 (Genentech), 2-Methoxyestradiol (Allergan / Oculex), DL-8234 (Toray Industries), NTC-200 (Neurotech), Tetrathiomolybdate (University of Michigan), LYN-002 (Lynkeus Biotech), Microalgae Compounds (Aquasearch / Albany, Mera Pharmaceuticals), D-9120 (Celitech Group plc), ATX-S10 (Hamamatsu Photonics), TGF-β2 (Genzyme / Celtrix), Tyrosine kinase inhibitors (such as those from Allergan, SUGEN, or Pfizer), NX-278-L (NeXstar Pharmaceuticals / Gilead Sciences), Opt-24 (OPTIS France SA), Retinal Ganglion Neuroprotective Agent (Cogent Neurosciences), N-Nitropyrazole Derivative (Texas A&M University System), and KP-102 (Krenitsky). Pharmaceuticals, cyclosporine A, therapeutic agents used in photodynamic therapy (e.g., VISUDYNE®; receptor-targeted PDT, Bristol-Myers Squibb, Co.; porfimer sodium for injection with PDT; verteporfin, QLT Inc.; rostaporfin with PDT, Miravent Medical Technologies; talaporfin with PDT, Nippon Petroleum; and motexafin lutetium, Pharmacyclics, Inc.), antisense oligonucleotides (including, for example, products tested by NovagaliPharma SA and ISIS-13650 of Isis Pharmaceuticals), and combinations thereof.

[0159] The anti-CFHR4 antibody or its antibody conjugates, fusion proteins, and / or polymer formulations disclosed herein can be administered in combination with therapies or surgical procedures to treat ocular conditions (e.g., AMD, GA, DME, DR, or RVO), including, for example, laser photocoagulation (e.g., panretinal photocoagulation (PRP)), drusen laser treatment, macular hole surgery, macular translocation surgery, implantable minimacular lenses, PHI-motion angiography (also known as micro-laser therapy and vascularization therapy), proton beam therapy, microstimulation therapy, retinal detachment and vitrectomy, scleral buckling, submacular surgery, transpupillary thermotherapy, photosystem I therapy, RNA interference (RNAi), in vitro rheological therapy (also known as membrane differentiation filtration and rheological therapy), microchip implantation, stem cell therapy, gene replacement therapy, ribozyme gene therapy (including gene therapy targeting hypoxia-responsive elements, Oxford Biomedica; Lentipak, Genetix; and PDEF gene therapy, GenVec), photoreceptor / retinal cell transplantation (including transplantable retinal epithelial cells, Diacrin, Inc.; retinal cell grafts, Cell Genesys, Inc.), acupuncture, and combinations thereof.

[0160] In some embodiments, the anti-CFHR4 antibody of this disclosure or its antibody conjugates, fusion proteins, and / or polymer formulations may be administered in combination with an anti-angiogenic agent to treat ocular conditions (e.g., AMD, GA, DME, DR, or RVO). Any suitable anti-angiogenic agent may be used in combination with the antibody of this disclosure, including but not limited to those listed in Carmeliet et al., Nature 407:249-257, 2000. In some embodiments, the anti-angiogenic agent is a VEGF antagonist, including but not limited to: anti-VEGF antibodies (e.g., anti-VEGF Fab LUCENTIS® (ranibizumab), RTH-258 (formerly known as ESBA-1008, an anti-VEGF single-chain antibody fragment; Novartis) or bispecific anti-VEGF antibodies (e.g., anti-VEGF / anti-angiogenic 2 bispecific antibodies, such as RG-7716; Roche)), soluble recombinant receptor fusion proteins (e.g., EYLEA® (aflibercept)), VEGF variants, soluble VEGFR fragments, aptamers capable of blocking VEGF (e.g., phenagatanib) or VEGFR, neutralizing anti-VEGFR antibodies, small molecule inhibitors of VEGFR tyrosine kinases, and anti-VEGFDARPin® (e.g., abicipapegoline). pegol), small interfering RNAs that inhibit VEGF or VEGFR expression, VEGFR tyrosine kinase inhibitors (e.g., 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidine-1-ylpropoxy)quinazoline (AZD2171), vatalani (PTK787), smannib (SU5416; SUGEN), and SUTENT® (sunitinib) and combinations thereof.

[0161] Other suitable anti-angiogenic agents that can be combined with the antibodies or antibody conjugates thereof, fusion proteins and / or polymer formulations disclosed herein for the treatment of ocular conditions (e.g., AMD, GA, DME, DR or RVO) include corticosteroids, angiotensin-releasing steroids, anecoxitol acetate, angiostatin, endostatin, tyrosine kinase inhibitors, matrix metalloproteinase (MMP) inhibitors, insulin-like growth factor binding protein 3 (IGFBP3), matrix-derived factor (SDF-1) antagonists (e.g., anti-SDF-1 antibodies), pigment epithelial-derived factor (PEDF), γ-secretase, delta-like ligand 4, integrin antagonists, hypoxia-inducible factor (HIF)-1α antagonists, protein kinase CK2 antagonists, agents that inhibit stem cell (e.g., endothelial progenitor cells) homing to new angiogenesis sites (e.g., anti-vascular endothelial cadherin (CD-144) antibodies and / or anti-SDF-1 antibodies) and combinations thereof.

[0162] In some embodiments, the anti-CFHR4 antibody or its antibody conjugate, fusion protein and / or polymer formulation disclosed herein may be administered in combination with an agent having anti-angiogenic activity to treat ocular conditions (e.g. AMD, GA, DME, DR or RVO), such as anti-inflammatory drugs, mammalian rapamycin target (mTOR) inhibitors (e.g. rapamycin, AFINITOR® (everolimus) and TORISEL® (tesiromolimus)), cyclosporine, tumor necrosis factor (TNF) antagonists (e.g., anti-TNFα antibodies or their antigen-binding fragments (e.g., infliximab, adalimumab, certolizumab pegol and golimumab) or soluble receptor fusion proteins (e.g., etanercept)), anticomplement agents, nonsteroidal anti-inflammatory agents (NSAIDs) or combinations thereof.

[0163] Any suitable AMD therapeutic agent may be administered as an additional treatment in combination with the anti-CFHR4 antibody or its antibody conjugates, fusion proteins and / or polymer formulations disclosed herein for the treatment of ocular conditions (e.g., AMD, GA, DME, DR, or RVO). The AMD therapeutic agents include, but are not limited to, VEGF antagonists, such as anti-VEGF antibodies (e.g., LUCENTIS® (ranibizumab), RTH-258 (formerly known as ESBA-1008, an anti-VEGF single-chain antibody fragment; Novartis) or bispecific anti-VEGF antibodies (e.g., anti-VEGF / anti-angiogenic 2 bispecific antibodies, such as RG-7716; Roche)), soluble VEGF receptor fusion proteins (e.g., EYLEA® (aflibercept)), anti-VEGFFDARPin® (e.g., arbexipar; MolecularPartners AG / Allergan), or anti-VEGF aptamers (e.g., MACUGEN®). (pigatanib sodium); platelet-derived growth factor (PDGF) antagonists, such as anti-PDGF antibodies, anti-PDGFR antibodies (e.g., REGN2176-3), anti-PDGF-BB pegylated aptamers (e.g., FOVISTA®; Ophthotech / Novartis), soluble PDGFR receptor fusion proteins, or dual PDGF / VEGF antagonists (e.g., small molecule inhibitors (e.g., DE-120 (Santen) or X-82 (TyrogeneX)) or bispecific anti-PDGF / anti-VEGF antibodies); VISUDYNE® Combinations of verteporfin with photodynamic therapy; antioxidants; complement system antagonists, such as complement factor C5 antagonists (e.g., small molecule inhibitors (e.g., ARC-1905; Opthotech) or anti-C5 antibodies (e.g., LFG-316; Novartis), properdin antagonists (e.g., anti-properdin antibodies (e.g., CLG-561; Alcon) or complement factor D antagonists (e.g., anti-complement factor D antibodies (e.g., lanpalizumab; Roche)); visual cycle modulators (e.g., emixustat hydrochloride); squalene (e.g., OHR-102; Ofr Pharmaceutical); vitamin and mineral supplements (e.g., those described in the Age-Related Eye Disease Study 1 (AREDS1; zinc and / or antioxidants) and Study 2 (AREDS2; zinc, antioxidants, lutein, zeaxanthin, and / or ω-3 fatty acids)); cell-based therapies, such as NT-501. (Renexus);PH-05206388 (Pfizer), huCNS-SC cell transplantation (StemCells), CNTO-2476 (Janssen), OpRegen (Cell CureNeurosciences), or MA09-hRPE cell transplantation (Ocata Therapeutics); tissue factor antagonists (e.g., hl-con1; Iconic Therapeutics); α-adrenergic receptor agonists (e.g., brimonidine tartrate); peptide vaccines (e.g., S-646240; Shionogi); β-amyloid antagonists (e.g., anti-β-amyloid monoclonal antibodies, e.g., GSK-933776); S1P antagonists (e.g., anti-S1P antibodies, e.g., iSONEP™; Lpath Inc); ROBO4 antagonists (e.g., anti-ROBO4 antibodies, e.g., DS-7080a; Daiichi). Sankyo); lentiviral vectors expressing endostatin and angiogenesis inhibitors (e.g., RetinoStat) and any combination thereof. In some cases, AMD treatments (including any of the foregoing AMD treatments) may be co-formulated. For example, the anti-PDGFR antibody REGN2176-3 may be co-formulated with aflibercept (EYLEA®). In some cases, this co-formulation may be administered in combination with the antibodies disclosed herein. In some cases, the ocular condition is AMD (e.g., wet AMD).

[0164] In addition to therapeutic uses, the anti-CFHR4 antibodies or antigen-binding fragments described herein can also be used for diagnostic or research applications. Research applications include, for example, methods using anti-CFHR4 antibodies and tags to detect CFHR4 in samples, such as human fluids or cell or tissue extracts. Anti-CFHR4 antibodies or their antigen-binding fragments can be used in any suitable assay to measure CFHR4 in a sample for diagnostic and / or research purposes. Such assays include, but are not limited to, sandwich immunoassays, enzyme immunoassays (EIA), enzyme-linked immunosorbent assays (ELISA), lateral fluid assays, competitive inhibition immunoassays (e.g., forward and reverse), competitive binding assays, Forster resonance energy transfer (FRET), one-step antibody assays, single-molecule assays, radioimmunoassays (RIA), and FACS. Such methods are disclosed, for example, in U.S. Patents 6,143,576; 6,113,855; 6,019,944; 5,985,579; 5,947,124; 5,939,272; 5,922,615; 5,885,527; 5,851,776; 5,824,799; 5,679,526; 5,525,524 and 5,480,792; and Adamczyk et al., Anal. Chim. Acta, 579(1): 61-67 (2006).

[0165] Anti-CFHR4 antibodies or their antigen-binding fragments are available in a kit, for example, a packaged combination of a predetermined amount of reagent and instructions for use in an assay (e.g., an assay for detecting CFHR4). Therefore, this disclosure provides a kit containing the antibody or antigen-binding fragment described herein and its instructions for use. The instructions may be in paper or computer-readable form, such as a disk, CD, DVD, etc. Alternatively or additionally, the kit may contain a calibrator or control, and / or at least one container (e.g., tube, microtiter plate, or test strip) for performing the assay, and / or buffers, such as assay buffers or wash buffers. Ideally, the kit contains all the components necessary to perform the assay, i.e., reagents, standards, buffers, diluents, etc. Additional additives may be included in the kit, such as stabilizers, buffers (e.g., blocking buffers or lysis buffers), etc. The relative amounts of various reagents can be varied to provide concentrations in the reagent solution, thereby significantly optimizing the sensitivity of the assay. Reagents may be provided in the form of dry powder (typically lyophilized powder), including excipients that, upon dissolution, will provide a reagent solution with an appropriate concentration.

[0166] The following examples further illustrate various embodiments of this disclosure, but should not be construed as limiting its scope in any way.

[0167] Example

[0168] It will be apparent to those skilled in the art that other suitable modifications and adaptations to the methods of this disclosure described herein are readily applicable and understandable, and that suitable equivalents may be used without departing from the scope of this disclosure or the aspects and embodiments disclosed herein. Having now been described in detail, this disclosure will be more clearly understood by referring to the following examples, which are intended only to illustrate some aspects and embodiments of this disclosure and should not be considered as limiting the scope of this disclosure. All journal references, U.S. patents, and published disclosures cited herein are hereby incorporated in their entirety by reference.

[0169] This disclosure has several aspects, which are illustrated by the following non-limiting embodiments.

[0170] Example 1

[0171] Genetic analysis of CFHR4 in geographic atrophy. This example describes an analysis performed in FinnGen to determine the impact of CFHR1 / 4 deletion on age-related macular degeneration (AMD). Three common haplotypes consist of variants in CFH (rs1061170 Y402H) and eQTL and pQTL variants of CFH and CFHR4 (rs10922109), which are associated with three different levels of risk. The high-AMD-risk haplotype (H402+ with high CFHR4 expression, rs106117_C(ref) / rs10922109_C(ref)) was set as the “reference” haplotype to allow comparison with other haplotypes (frequency in cases: 0.56, frequency in controls: 0.36). The haplotype carrying Y402 (the alternative allele at rs106117) with high CFHR4 / low CFH expression (the reference allele at rs10922109) was associated with an "intermediate" risk of AMD (frequency in cases: 0.196, frequency in controls: 0.21). The "low" risk haplotype carrying Y402 (the alternative allele at rs106117) with low CFHR4 / high CFH expression (the alternative allele at rs10922109) had a frequency of 0.22 in cases and 0.43 in controls. It is speculated that the risk of AMD may differ in haplotypes carrying CFHR1 / 4 deletions within an intermediate-risk context.

[0172] The genetic variation at this locus provides a natural experiment to determine the impact of CFHR1 / 4 deletion on AMD. CFHR1 / 4 deletion is not directly genotyped in FinnGen, but variants (rs528922402 and rs188297593) exist that are imperfectly labeled (r² = 0.36, D' = 1 in Finland) in the non-overlapping subset of the deletion in the Finnish population of the 1000 Genomes dataset (HapMap phase 3). Variant rs188297593 has D' < 1.0 in HapMap Phase 3 samples of European ancestry (1 of 4 carriers was not labeled with CFHR1 / 4 deletion). These two variants capture a subbase of the deletion but not all carriers.

[0173] To determine the effects of CFH variants (rs1061170), CFHR4 / CFH eQTL / pQTL (rs10922109), and CFHR1 / 4 deletions (labeled rs528922402 and rs188297593), individuals in FinnGen R6 underwent AMD risk checks. Haplotypes composed of individual variants were generated, and logistic regression was run in R to predict the haplotype's effect on AMD risk, adjusted for sex, age, and PC. A reference haplotype was used as a reference, such that all other haplotype effects were associated with that haplotype.

[0174] Consistent with the assumption that CFHR4 directly causes AMD risk, the "medium risk" haplotype lacking CFHR4 provides increased protection against AMD compared to the "medium risk" haplotype with full CFHR4.

[0175] Table 1: Results of haplotype analysis in FinnGen showing the AMD risk for each haplotype, as well as the odds ratio and p-value for logistic regression.

[0176]

[0177] Example 2

[0178] Generation of recombinant CFHR4 protein. Recombinant protein preparation is performed to generate specific proteins that can be used as immunogens / antigens, screening reagents, and / or control reagents. All efforts are aimed at generating a set of anti-CFHR4b antibodies with desired properties.

[0179] Proteins with sequences corresponding to human CFHR4b, human CFHL-1 wild-type, human CFHL-1 with a tyrosine 402 mutation to histidine, and cynomolgus monkey CFHR4b were successfully generated using various protein tags. Upon completion, all protein preparations achieved a purity exceeding 90% and contained less than 1 endotoxin unit per milliliter, as determined by analytical methods. Examples of the final specifications of individual formulations are shown below.

[0180] The study began with computer analysis, identifying and extracting appropriate wild-type amino acid sequences for human and cynomolgus monkey CFHR4b and human CFHL-1 from publicly available databases. Following the project plan, the sequences were then further analyzed and manually modified using Geneious Prime software. The sequences were examined for defects and modified to add further amino acid sequences encoding “tags” that facilitate purification, reduce immunogenicity, or simplify analytical screening. Examples of protein tags used in this study included the HIS tag, the proprietary mouse IgG Fc tag, and the Avi tag. The tags were separated from each other and from the CFHR4b or CFHL-1 sequences by short linker sequences. All tags were added to the C-terminus of the sequences. Furthermore, the native signal peptide was removed and replaced with a signal peptide that facilitated recombinant expression.

[0181] After all modifications were completed, the amino acid sequences were translated back into DNA sequences and optimized for codon biases found in the human genome. These optimized DNA sequences were sent to Integrated DNA Technologies, which produced DNA fragments with DNA overhangs added to the 5' and 3' ends. Using the DNA overhangs and the Gibson cloning method, these DNA fragments were assembled into the desired sequence and cloned into a mammalian expression plasmid driven by the CMV promoter. The plasmid was propagated in *E. coli* using appropriate antibiotic selection and prepared at a scale suitable for recombinant expression using a commercially available preparation kit from Qiagen. The sequences of the plasmid and the expressed gene were then confirmed using Sanger sequencing.

[0182] Using polyethyleneimine, sequence-validated plasmids were transfected into human embryonic kidney cells suitable for recombinant protein expression. One day after transfection, the cells were supplemented with chemicals and nutrients designed to increase the expression of the recombinant protein. These supplements included sodium propionate, valproic acid, glucose, glutamine, and various yeast lysates. Five days after transfection, the expression cell culture was harvested. As the recombinant protein was secreted into the growth medium, cells, cell fragments, and cell debris were removed by centrifugation and filtration through a membrane with a pore size no larger than 0.22 micrometers. The clarified medium conditioned with the recombinant protein was now ready for purification.

[0183] Proteins of interest were purified from cell culture medium and immobilized on the column using FPLC (Rapid Pressurized Liquid Chromatography) and a suitable commercially available pre-packed affinity column (for C-terminal tags). For HIS-tagged proteins, a Ni-NTA agarose column was used. For Fc-tagged proteins, a proA agarose column was used. Multiple column washes were then performed, each tailored to the column / tag / chromatogram type. For HIS-tagged proteins, the protein of interest was eluted from the column with 300 mM imidazole, and for Fc-tagged proteins, it was eluted with 100 mM citrate at pH 3.5. After elution, the pH of Fc-tagged proteins was adjusted to neutral using 1 M Hepes at pH 9. Neutralization was not required for HIS-tagged proteins as the elution buffer was neutral.

[0184] Protein quality and quantity were assessed using a combination of SDS-PAGE gel electrophoresis, spectrophotometry, and analytical-SEC (size exclusion chromatography). Most proteins used in this project required further purification. FPLC and a second column were employed for further protein refinement. Size separation was achieved using a size exclusion column, which enabled protein purity >90%. SEC also facilitated buffer exchange between affinity chromatography elution buffer and a final selected buffer (PBS). Protein samples were then subjected to quality control. If increased protein concentration was required at any point during purification, proteins were concentrated by separating them from the buffer using an Amicon Ultra molecular weight cutoff (MWCO) filter. MWCO was selected to ensure size compatibility with the proteins of interest. All final samples were concentrated to >1 mg / mL before proceeding to final quality control.

[0185] Endotoxin contamination in the final protein samples was determined using Charles River's Endosafe PTS system. The final protein concentration was determined spectrophotometrically. Three micrograms of the final sample were injected into an analytical SEC column (YMC Diol 300) to determine its final purity. Additionally, SDS-PAGE electrophoresis was sometimes performed to determine the final quality. Once all final parameters passed, the proteins were sterilized using a 0.22-micron sterile filter in a biosafety cabinet. They were then aseptically aliquoted and rapidly frozen in liquid nitrogen, and then stored at -80°C.

[0186] Example 3

[0187] The CFHR4 antibody sequence was recovered from immunized mice. CFHR4 immunization: Alloy Therapeutic transgenic humanized mice (ATX-GK) in three cohorts were immunized with human CFHR4b using the following 5-week protocol. Figures 3A to 3C ):

[0188] Cohort 1: ATX-GK mice were immunized with human CFHR4B (ATX-P-57) using the standard 5-week RIMMS protocol: 10 μg of antigen emulsified in complete Freund's adjuvant was administered subcutaneously, followed by weekly subcutaneous administration of antigen emulsified in incomplete Freund's adjuvant for 5 weeks. Cohort 2: Five ATX-GK mice were immunized with human CFHR4B (ATX-P-57) using the 5-week RIMMS protocol: 10 μg of antigen emulsified in incomplete Freund's adjuvant was administered subcutaneously weekly. Cohort 3: Five ATX-GK mice were immunized with human CFHR4B (ATX-P-57) using the 5-week RIBI IP protocol: 10 μg of antigen emulsified in RIBI adjuvant was administered intraperitoneally weekly.

[0189] Blood samples were collected in the fourth week, and the titers of antigen-positive and purified-labeled negative serum were tested by ELISA. ELISA plates were coated with 1 μg / ml CFHR4 immunogen or an unrelated protein (P114) with the same purified label as the immunogen. The antigen-coated plates were incubated with seven 10-fold serial dilutions of serum (starting from 1:300). Antibodies binding to the antigen were detected using anti-mouse IgG HRP secondary antibody and a one-step TMB solution. The absorbance signal at 450 nm was measured using an ELISA microplate reader.

[0190] Hybridoma: Immunological tissues from high-titer mice were harvested and preserved for antibody discovery. Hybridoma cell lines producing CFHR4 antibodies were generated by fusing single B cells from the spleen and lymph nodes of titer-positive mice with myeloma cells. Twenty 96-well plates of hybridoma fusions were generated and expanded. Hybridomas expressing CFHR4-specific antibodies were detected by antigen binding via ELISA. The affinity of the antibody in the hybridoma supernatant was measured by SPR using an Octet instrument. The CFHR4 antibody in the hybridoma supernatant was loaded onto a biosensor. The reaction was measured as a nm shift in the interference pattern and was proportional to the amount of antibody bound to the biosensor surface. The binding interaction of CFHR4 with the immobilized antibody was measured as association (kon). After analyte association, the biosensor was immersed in CFHR4-free PBS, allowing the bound antigen to dissociate from the antibody (kdis). KD(M), or antibody affinity for CFHR4, was measured as kdis / kon. The heavy and light chains of the validated hybridomas were sequenced. RNA was isolated from hybridomas secreting CFHR4 antibodies and cloned from both the heavy and light chain variable regions by reverse transcription using gene-specific primers followed by PCR amplification using variable strand gene-specific primers. The PCR products were sequenced using standard Sanger sequencing methods.

[0191] Phage display: Variable heavy and light chains were amplified from the spleens of high-titer immunized mice using reverse transcription with gene-specific primers followed by PCR amplification with variable strand gene-specific primers. The variable region was cloned into a phage display vector designed to express Fab on the phage g3p protein. A phage library expressing unique Fab was amplified and purified. Phages were allowed to bind to biotinylated CFHR4 antigen captured on streptavidin beads. Phages still bound to the antigen beads after several rigorous washes were eluted with alkaline triethylamine solution and neutralized with Tris buffer at pH 8.0. The eluted phages were re-infected into TG1 bacterial cells, amplified by co-infection with M13 helper phages, and purified by PEG precipitation. Purified phages expressing Fab were selected for antigen binding as described. A second round of phage dilution and infection was performed into TG1 cells. The phage polyclonal pools generated from the two rounds of panning were tested by ELISA to confirm the presence of CFHR4-specific phages. Rolling circle amplification and standard Sanger sequencing were used to sequence the variable heavy and light chain regions of a single infected bacterial colony.

[0192] Antibody Sequencing: Unique variable heavy and light chain pairs from hybridoma and phage display activities were cloned into a vector designed to express full-length antibodies as IgG in HEK293 cells under the control of a CMV promoter. The antibody expression vector was conjugated with polyethyleneimine and transfected into HEK293 cultures. After 5 days of shaking at 37°C in HEK293 cell culture medium, the antibody was captured on agarose-based protein A resin. After several rigorous washes, the antibody was eluted in glycine solution at pH 3, neutralized with Hepes at pH 9, and the buffer was exchanged for PBS.

[0193] Example 4

[0194] Differential scanning fluorescence (DSF) for human CFHR4 monoclonal antibodies. The development of effective monoclonal antibodies depends not only on their biological activity but also on their physicochemical properties, such as homogeneity and stability. The stability of mAbs can be affected by their formulation. Among the many techniques used to study mAb stability, differential scanning fluorescence (DSF) offers excellent throughput and minimal material consumption. DSF measures the temperature (Tm) of protein unfolding transition based on changes in the fluorescence intensity of environmentally sensitive dyes.

[0195] Experiments were conducted to assess the thermal stability of the human CFHR4 monoclonal antibody (“ATX” antibody) of this disclosure by determining the melting temperature. Thermal stability was assessed via differential scanning fluorometry (DSF) using a Protein Thermal Shift (PTS) assay from Applied Biosystems. The assay was performed according to the manufacturer’s instructions. Briefly, the antibody to be evaluated was prepared in triplicate by mixing the antibody to be evaluated with a protein thermal shift dye and buffer; real-time melting experiments from 25°C to 95°C were performed on a QuantStudio 3. Data were analyzed using protein thermal shift software, and the melting temperature (Tm) was calculated from the melting curve. Figure 4 ).

[0196] Table 2: DSF analysis of human anti-CFHR4 monoclonal antibody.

[0197]

[0198] Example 5

[0199] CFHR4 antibody cross-blocking. High-throughput epitope binning experiments were performed on a real-time label-free biosensor (Carterra LSA), sorting a large number of mAbs into bins based on their ability to block each other's binding to antigens. In pairwise epitope binning analysis, antigen and antibody 2 (analyte antibody) were sequentially applied to a sensor chip (HC200M) covalently preloaded with antibody 1 (ligand antibody). An increased response after exposure to the analyte antibody indicated no competition between the two antibodies, while a lack of signal change indicated competition. Antibodies in the test set that had the same blocking characteristics against other antibodies were grouped into bins. Community network graphs were used to explore clustering of mAbs with similar but not necessarily identical competitive characteristics. This was done in conjunction with interlayer / blocking assignments that were not strictly dependent on the heatmap. Figure 5A Unlike the bin network plot, hierarchical clustering is applied to the sorted heatmap to generate the network plot. Figure 5B The network graph progressively groups mAbs.

[0200] Example 6

[0201] CFHR4 antibody binding kinetics. Kinetic experiments were performed on a Carterra LSA with a running buffer of PBS, pH 7.40, 1% BSA, and 0.05% Tween 20. The antibody was covalently printed onto an HC30M chip. The chip was activated for 7 min with 33 mM s-NHS in 100 mM MES, pH 5.5 and 133 mM EDC. 10 mg / ml of antibody in acetate buffer at pH 4.5 was used for printing for 10 min. The printed chip was then quenched for 7 min with 1 M ethanolamine, pH 8.5. For kinetic analysis, purified recombinant His-tagged protein ATX-P-57 (human CDFR4B-His) was sequentially injected at concentrations from 0.076 nM to 1500 nM (serial 3-fold dilutions). For each concentration, association was performed for 5 min, followed by dissociation for 15 min. Results were processed and analyzed using Carterra LSA kinetic software. Kinetic data were referenced to a gap reference point and looped through a double-reference buffer, and then globally fitted to a 1:1 binding model to determine their apparent association and dissociation kinetic rate constants (ka and kd values). The ratio kd / ka was used to derive the KD value for each antigen / mAb interaction, i.e., KD = kd / ka. Figure 6 ).

[0202] Example 7

[0203] CFHR4 antibody cross-reactivity. Experiments were conducted to determine the reactivity of the CFHR4 antibody of this disclosure (developed using the CFHR4b antigen; see Example 3) with various other CFHR4 proteins. Figure 7 As shown, experiments were conducted to determine the reactivity of the CFHR4 antibody with the cynomolgus monkey CFHR4b protein (cCFHR4b). Binding assays were performed on a Carterra LSA with a running buffer of PBS, pH 7.40, 1% BSA, and 0.05% Tween 20. The antibody was covalently printed onto an HC30M chip. The chip was activated for 7 min with 100 mM MME S, pH 5.5, 33 mM s-NHS, and 133 mM EDC. 10 mg / ml of antibody in acetate buffer at pH 4.5 was used for printing for 10 min. The printed chip was then quenched for 7 min with 1 M ethanolamine at pH 8.5. For reactivity assays, 160 nM ATX-P-141 (cyno CFHR4B-mFc) associated for 5 min, followed by dissociation for 15 min. Results were processed and analyzed using Carterra LSA kinetic software. Data were cycled with a gap reference point and double reference buffer, and the post-association response (nm) was then reported. Isotype controls are used to determine the cutoff response for positive binding.

[0204] Experiments were also conducted to determine the reactivity of the CFHR4 antibody with human CFHR4a protein. Figure 8 Binding assays were performed on a Carterra LSA with a run buffer of PBS, pH 7.40, 1% BSA, and 0.05% Tween 20. Antibodies were covalently printed onto an HC30M chip. The chip was activated for 7 min with 33 mM s-NHS and 133 mM EDC in 100 mM MES, pH 5.5. Antibody in 10 mg / ml acetate buffer at pH 4.5 was used for printing for 10 min. The printed chip was then quenched for 7 min with 1 M ethanolamine, pH 8.5. For reactivity assays, 540 nM ATX-P-56 (human CFHL4A-His) was used for association at 5 min, followed by dissociation at 15 min. Results were processed and analyzed using Carterra LSA kinetic software. Data were cycled with a gap reference point and double reference buffer, and the post-association response (nm) was then reported. An isotype control was used to determine the cutoff response for positive binding.

[0205] Experiments were also conducted to determine the reactivity of the CFHR4 antibody with the human CFHR3 protein. Figure 9Binding assays were performed on a Carterra LSA with a run buffer of PBS, pH 7.40, 1% BSA, and 0.05% Tween 20. Antibodies were covalently printed onto an HC30M chip. The chip was activated for 7 min with 33 mM s-NHS and 133 mM EDC in 100 mM MES, pH 5.5. Antibody in 10 mg / ml acetate buffer at pH 4.5 was used for printing for 10 min. The printed chip was then quenched for 7 min with 1 M ethanolamine, pH 8.5. For reactivity assays, 550 nM ATX-P-58 (human CFHL3-His) was used for association at 5 min, followed by dissociation at 15 min. Results were processed and analyzed using Carterra LSA kinetic software. Data were cycled with a gap reference point and double reference buffer, and the post-association response (nm) was then reported. An isotype control was used to determine the cutoff response for positive binding.

[0206] Experiments were also conducted to determine the reactivity of the CFHR4 antibody with the human CFHL-1 (Y402H) protein. Figure 10 Binding assays were performed on a Carterra LSA with a run buffer of PBS, pH 7.40, 1% BSA, and 0.05% Tween 20. Antibodies were covalently printed onto an HC30M chip. The chip was activated for 7 min with 33 mM s-NHS and 133 mM EDC in 100 mM MES, pH 5.5. Antibody in 10 mg / ml acetate buffer at pH 4.5 was used for printing for 10 min. The printed chip was then quenched for 7 min with 1 M ethanolamine, pH 8.5. For reactivity assays, 380 nM ATX-P-421 (human CFHL1-Y402H-His) was used for association at 5 min, followed by dissociation at 15 min. Results were processed and analyzed using Carterra LSA kinetic software. Data were cycled with a gap reference point and double reference buffer, and the post-association response (nm) was then reported. An isotype control was used to determine the cutoff response for positive binding.

[0207] Example 8

[0208] C3 convertase assembly assay. A screening assay was developed to evaluate the ability of the CFHR4 antibody disclosed herein to affect C3 convertase formation. Figure 11AC3bBb is a C3 convertase (EC 3.4.21.43) of the complement activation alternative pathway. The C3 enzyme is responsible for amplification pathway activation and the deposition of the C3b and membrane attack complex on target cells. It is controlled by serum protein factors H, factor I (EC 3.4.21.45), and serum sterilization proteins. The formation of C3 convertase requires C3b, factor B, factor D (EC 3.4.21.46), and Mg2+. After the formation of the reversible bimolecular complex C3bB(Mg), factor D cleaves factor B, releasing the activating fragment Ba, and generating the active enzyme C3bBb. The C3 enzyme is a serine protease with its catalytic site located in the Bb subunit. Additionally, CFHR4 has been reported to directly promote the formation of C3 convertase by binding to C3b, exhibits a stronger ability to assemble C3bBb on CFHR4, and the C3bBb-CFHR4 complex is more resistant to CFH cleavage compared to C3bBb.

[0209] Therefore, the assay aims to test the ability of the CHFR4 antibody to disrupt the formation of the C3 convertase complex by measuring the amount of factor B present using an anti-FB monoclonal antibody conjugated to the reporter portion. Figure 11A As illustrated, in the presence of CFHR4 (but without an effective CFHR4 antibody), a C3 convertase complex is formed, and the anti-FB antibody binds to FB and a signal is detected (i.e., complement activation). However, in the presence of an effective anti-CFHR4 antibody, the C3 convertase complex is disrupted, and the antibody-bound FB is washed away, resulting in a weakened signal (i.e., no complement activation).

[0210] Below is an example of a measurement protocol:

[0211] Preparation of FHR-4 coated plates— (1) Coat the plates with 5 μg / ml FHR-4 in PBS and incubate overnight in a plastic bag with wet paper at room temperature. (2) Wash 3 x 300 μl with Wieslab washing buffer. (3) Block the wells with 150 μl of 3% BSA in PBS. (4) Incubate at room temperature for at least 1 h. (5) Aspirate the wells and wash with 1 x 300 μl of Superblock. (6) Dry the plates at 37°C and 16% RH for at least 1 h. (7) Store the plate bags in a refrigerator.

[0212] Assay Protocol— (1) Place the diluent, plate, substrate, and stop solution at room temperature. (2) Dilute the anti-OVA antibody to the required concentration in AP diluent. (3) Add 50 μl of anti-OVA, AP diluent (blank), and diluent control to the plate. (4) Cover and incubate at room temperature for 1 h. (5) Wash with 3 x 300 μl of Wieslab wash buffer. (6) Add 50 μl of 5 μg / ml C3b or AP diluent to the plate. (7) Incubate the plate at 37°C for 30 min. (8) Wash with 3 x 300 μl of Wieslab wash buffer. (9) Add 50 μl of a protein mixture (FB, FD, serum sterile protein) to the plate. (10) Incubate the plate at 37°C for 30 min. (11) Wash with 3 x 300 μl of Wieslab wash buffer. (12) Add 50 μl of anti-factor B antibody diluted 1:2000 in AP dilution buffer to the entire plate. (13) Incubate at room temperature for 1 h. (14) Wash with 3 x 300 μl of Wieslab wash buffer. (15) Add 50 μl of rabbit anti-goat IgG-HRP antibody diluted 1:5000 in Stabilzyme to the entire plate. (16) Incubate at room temperature for 1 h. (17) Wash with 3 x 300 μl of Wieslab wash buffer. (18) Add 50 μl of substrate to the entire plate. (19) Incubate at room temperature for 20 min. (20) Add 50 μl of stop solution to the entire plate. (21) Read the plate at 450–620 nm.

[0213] like Figure 11B As shown, dose-response curves were generated for the top 8 inhibitory antibodies screened in the C3 convertase assembly assay. The percentage of C3 convertase activity relative to the negative control (diluted only) was plotted. Figure 11C Including targeting Figure 11B The IC50 value was calculated for each antibody tested. Figure 11D A representative summary of data for anti-CFHR4 antibodies, showcasing at least three functional classes, is provided.

[0214] sequence

[0215] The following section provides the various amino acid and nucleic acid sequences cited in this article.

[0216] Table 3: Anti-CFHR4 antibody (CDR sequence)

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223] Table 4: Anti-CFHR4 antibody (VH and VL sequences)

[0224] SEQ ID NO: Antibody name: Descriptor: sequence: 260 ATX-P-583 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYGISWVRQAPGQGLEWMGWISAYSGNTHYAQSLQDRVTMTTDTSSTAYMEVRSLRSDDTAVYYCAKDEGYCSSTGCLNLFDPWGQGTLVTVSS 261 ATX-P-591 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTAYMELRSLRSDDTAIYYCTRDLRGTAFDYWGQGTPVTVSS 262 ATX-P-602 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNYAKKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGDTIFRLVTPLDYWGQGTLVTVSS 263 ATX-P-597 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYMQWVRQAPGQGLEWLGIIDPSGGSTTYAQKFQGRVTMTRDTSTSTVHMELRSLRSEDTAVYYCARDEGTDRPGWGYWGQGTLVTVSS 264 ATX-P-601 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTNYAQKFQGRLTMTRDTSTNTVYMELSSLRSEDTAVYYCATDQSGGMDVWGKGTTVTVSS 265 ATX-P-607 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTNTVYMELSSLRSEDTAVYYCARDPEYSSAFDIWGQGTMVTVSS 266 ATX-P-583 VH - Nucleotide CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCACCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAGTGGTAACACACACTATGCACAGAGCCTCCAGGACAGAGTCACCATGACCACAGACACATCCACGAGTACAGCCTACATGGAGGTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAAAGATGAGGGATATTGTAGTAGTACCGGCTGCTTAAACTTGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 267 ATX-P-591 VH - Nucleotide CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACTGCCATTTATTACTGTACGAGAGATCTACGTGGAACTGCCTTTGACTACTGGGGCCAGGGAACCCCGGTCACTGTCTCCTCA 268 ATX-P-602 VH - Nucleotide CAGGTGCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCAAAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGTTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGGGGATACGATTTTTCGACTGGTTACCCCTCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 269 ATX-P-597 VH - Nucleotide CAGGTGCAGCTGGTGCAATCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACACCTTCACCAACTACTATATGCAGTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGCTGGGAATAATCGACCCTAGTGGTGGTAGCACAACCTATGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCCACATGGAGCTGAGAAGTCTGAGATCTGAGGACACGGCCGTCTATTATTGCGCGAGAGATGAGGGAACAGATCGTCCCGGGTGGGGCTACTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 270 ATX-P-601 VH - Nucleotide CAGGTGCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACACCTTCACCAGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAATAATCAACCCTAGTGGTGGTAGCACAAACTACGCACAGAAGTTCCAGGGCAGACTCACCATGACCAGGGACACGTCCACGAACACAGTCTACATGGAACTGAGTAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGACAGATCAAAGTGGGGGGATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 271 ATX-P-607 VH - Nucleotide CAGGTGCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACACCTTCACCAGTTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAATAATCAACCCTAGTGGTGGTAGCACAAGCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCAACGAACACAGTCTACATGGAGCTGAGCAGCCTTCGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGATCCCGAGTATAGCAGTGCTTTTGATATCTGGGGACAAGGGACAATGGTCACCGTCTCCTCA 272 ATX-P-583 VL DIQMTQSPSSLSASVGDRVTITCRASQNIGSYLNWYQQKPGNAPKLLIYATSTLQSGVPSRFSGSGSGTDFTLIISSLHPEDFTVYYCQQSFIIPFTFGPGTKVDIK 273 ATX-P-591 VL DIQMTQSPSSLSASVGDRVTITCRASQSINTYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYSCQHSFTTPFTFGPGTKLEIK 274 ATX-P-602 VL EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTQFTLTISSLQSEDFAVYYCQQYGSSPWTFGQGTKVDIK 275 ATX-P-597 VL DIQMTQSPSSLSASIGDRVTITCRASQSISSYLDWYQRKSGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVDIK 276 ATX-P-601 VL DIQMTQSPSSLSASVGDRVTITCRASQSINIYLNWYQQKPEKDPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISNLQPEDFATYYCQQSYSTPITFGQGTRLEIK 277 ATX-P-607 VL DIQMTQSPSSLSASVGDRGTITCRASQSIRSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYRTPVTFGPGTKVDIK 278 ATX-P-583 VL - Nucleotide GACATCCAGATGACCCAGTCTCCGTCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAACATTGGCAGTTATTTAAATTGGTATCAGCAGAAACCAGGGAATGCCCCTAAACTCCTGATCTATGCTACATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCATCATCAGCAGTCTGCACCCTGAAGATTTTACAGTTTATTACTGTCAACAGAGTTTCATTATCCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 279 ATX-P-591 VL - Nucleotide GACATCCAGATGACTCAGTCTCCATCCTCCCTGTCTGCATCTGTTGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAACACCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTCCTGTCAACATAGTTTCACTACCCCATTCACTTTCGGCCCTGGGACCAAGCTGGAAATCAAA 280 ATX-P-602 VL - Nucleotide GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGTAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACACAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATGGTAGCTCACCGTGGACGTTCGGCCAAGGGACCAAAGTGGATATCAAA 281 ATX-P-597 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTATTGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAGATTGGTATCAGCGGAAATCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCGCTCACTTTCGGCGGAGGGACCAAAGTGGATATCAAA 282 ATX-P-601 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAATATCTATTTAAATTGGTATCAGCAGAAACCAGAGAAAGACCCTAAGCTCCTGATCTATGCTGCGTCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAATCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA 283 ATX-P-607 VL - Nucleotide GACATCCAGATGACACAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGGCACCATCACTTGCCGGGCAAGTCAGAGCATTAGAAGTTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGAACCCCAGTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 284 ATX-P-564 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYTMNWVRQAPGKGLEWVSSISSSSSYTYYADSVRGRFTISRDNAKNSLYLQMSSLRAEDTAVYYCARSASIAAGMDVWGKGTTVTVSS 285 ATX-P-568 VH EVQLVESGGGLVQPGGSLRLSCAASGFPFSSYVMSWVRQAPGKGLEWVSVISVSGGSTFYADSVRGRFTISRDNSKNTLYLQVYSLRAEDTAVYYCAKDGLAVAGFDHWGQGTLVTVSS 286 ATX-P-574 VH EVQLVESGGGLVQRGGSLRLSCVASGFTFSSYAMSWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDDSKKTLYLQMNSLRAEDTAVYYCAKRGDYGDYMDVWGKGTTVTVSS 287 ATX-P-565 VH QVQLVESGGGVVQPGRSLRLSCAASGFTFNTYGIHWVRQAPGKGLEWVAVIWHDGSSKNYVDSVTGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARRGNWNYGFYYYYMDVWGKGTTVTVSS 288 ATX-P-578 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYSMNWVRQAPGKGLEWVSYISSSSSTIFHADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCARGNWNYYYMDVWGKGTTVTVSS 289 ATX-P-569 VH EVQLVESGGGLAQFGRSLRLSCAASGFTFDDYAMHWLRQAPGMGLEWVSGISWNSGSIGYADSVKGRFTIARDNAKNSVHLQMNSLRAEDTALYYCAKDIGNGYTKGDVFDIWGQGTMVTVSS 290 ATX-P-576 VH EVQLVESGGGLVQPGRSLRLSCTASGFTFDDYEMHWVRQAPGKGLEWVSDISRNSGRIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDIWGSGYFDYWGQGILVTVSS 291 ATX-P-588 VH EVQLVESGGGLVQPGRSLRLSCAASGFTFEDYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCTKDRDDGYNYAGVFDYWGQGTLVTVSS 292 ATX-P-596 VH EVQLVESGGGLVQPGRSLRLSCAASGFSFDDYAMHWVRQVPGKGLEWVSGISWTGGSVGYADPVKGRFTISRDNAKNSLYLQMNSLRPEDTALYYCAKDMGDGYSRNWPFDYWGQGTLVTVSS 293 ATX-P-600 VH EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQVPGRGLEWVSGISWSGGSIGYADSVKGRFTISRDNSKNSLYLQMNSLRAEDTALYYCTKDREDGYNYGGVFDYWGQGTLVTVSS 294 ATX-P-564 VH - Nucleotide GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATACCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGTCATCCATTAGTAGTAGTAGTAGTTACACATACTACGCAGACTCAGTGAGGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAGCAGCCTGAGAGCCGAGGACACAGCTGTGTATTACTGTGCGAGATCGGCGAGTATAGCAGCTGGGATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 295 ATX-P-568 VH - Nucleotide GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCCCCTTTAGCAGCTATGTCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATAAGTGTTAGTGGTGGTAGTACATTCTACGCAGACTCCGTGAGGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAGTGTACAGCCTGCGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGATGGTTTGGCAGTGGCTGGTTTTGACCACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 296 ATX-P-574 VH - Nucleotide GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCGGGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTTAGTAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTAGTGGTAGTGGTGGTACCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACGATTCCAAGAAGACACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTATTGTGCGAAAAGGGGTGACTACGGGGACTACATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 297 ATX-P-565 VH – Nucleotide CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAATACCTATGGCATCCACTGGGTCCGCCAGGCTCCAGGCAAGGGACTGGAGTGGGTGGCAGTTATATGGCATGATGGAAGTAGTAAAAACTATGTAGACTCCGTGACGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGCGAGAAGGGGTAACTGGAACTACGGCTTCTACTACTACTACATGGACGTCTGGGGCAAAGGAACCACGGTCACCGTCTCCTCA 298 ATX-P-578 VH – Nucleotide GAGGTGCAGCTGGTGGAGTCTGGGGGAGGTTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTAGTAGTACCATTTTCCATGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACTCACTGTACCTGCAAATGAACAGCCTGAGAGACGAGGACACGGCTGTGTATTACTGTGCGAGAGGGAACTGGAACTACTACTACATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA 299 ATX-P-569 VH – Nucleotide GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGCACAGTTTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGCTCCGGCAAGCTCCAGGGATGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGCGGGAGCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCGCCAGAGACAACGCCAAGAACTCCGTGCATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATATAGGAAATGGATATACGAAGGGTGATGTTTTTGATATCTGGGGACAAGGGACAATGGTCACCGTCTCTTCA 300 ATX-P-576 VH – Nucleotide GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACATTTGATGATTATGAAATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGATATTAGTCGGAACAGTGGTAGAATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATTTCCAGAGACAACGCCAAGAACTCCCTGTATCTACAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATATTTGGGGATCGGGGTACTTTGACTATTGGGGCCAGGGAATCCTGGTCACCGTCTCCTCA 301 ATX-P-588 VH – Nucleotide GAAGTGCAGCTGGTGGAGTCCGGGGGAGGCTTGGTACAACCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGAAGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAAATCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTATATTACTGTACAAAAGATAGAGATGATGGCTACAACTATGCGGGGGTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCA 302 ATX-P-596 VH – Nucleotide GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCAGTTTTGATGATTATGCCATGCACTGGGTCCGGCAAGTTCCAGGGAAGGGCCTGGAATGGGTCTCAGGTATTAGTTGGACTGGTGGTAGCGTAGGCTATGCGGACCCCGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGACCTGAGGACACGGCCTTGTATTACTGTGCAAAAGATATGGGAGACGGGTATAGCAGAAACTGGCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 303 ATX-P-600 VH - Nucleotide GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGTTCCAGGGAGGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAGTGGTGGCAGCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACTCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTACAAAAGATAGAGAAGATGGATACAACTATGGGGGGGTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 304 ATX-P-564 VL DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSTGYNFLDWYLQKPGLSPQLLIYLASNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQGTKLEIK 305 ATX-P-568 VL DIQMTQSPSTLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIHKASGLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSFSLIFGGGTRVEIK 306 ATX-P-574 VL DIQMTQSPSSVSASVGDRVTITCRASQGITTWLAWYQQKPGKAPKLLIFGASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPWTFGQGTKVEIK 307 ATX-P-565 VL DIVMTQSPLSLPVTPGEPASISCRSSQRLLHSSGYNYLDWYLQKPGQSPQLLIYLGSSRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGLQTPPTFGQGTKVEIK 308 ATX-P-578 VL DIQMTQSPSTLSASVGDRVTISCRASQSVNSWLAWYQQKPGKAPKLLIYKASNLEGGVPSSFSGSGSGTEFTLTISSLQPDDFATYYCQQYDTSWTFGQGTKVEIK 309 ATX-P-569 VL DIQMTQSPSTLSASVGDSVTITCRASQNIITWLAWYQQKPGKAPNLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYSSYSYTFGQGTKLEIK 310 ATX-P-576 VL DIQMTQSPSSVSASVGDRVTITCRTSQGIRNWLAWYQQKPGKAPKLLIYAASSLQTGGPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPYTFGQGTKLEIK 311 ATX-P-588 VL EIVLTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFTFGPGTKVDIK 312 ATX-P-596 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYGSSPMYTFGQGTKLEIK 313 ATX-P-600 VL EIVLTQSPGTLSLSPGERATLSCRASQNVRGSYLAWYQQKPGQAPRLLIYGASNRATDIPDRFSGSGSGTDFTLTISGLEPEDFVVYYCQQYGSSYTFGQGTKVEIK 314 ATX-P-564 VL - Nucleotide GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTACTGGATACAACTTTTTGGATTGGTACCTGCAGAAGCCAGGGCTGTCTCCACAGCTCCTGATCTATTTGGCTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACAAACTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 315 ATX-P-568 VL – Nucleotide GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCCTCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGCCAGAGTATTAGTACCTGGTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATAAGGCGTCTGGTTTAGAAAGTGGGGTCCCATCAAGATTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTTTTCTCTCATTTTCGGCGGAGGGACCAGGGTGGAGATCAAA 316 ATX-P-574 VL – Nucleotide GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTACCACCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTGGTGCATCTAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACAGTTTCCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 317 ATX-P-565 VL – Nucleotide GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGCGCCTCCTGCATAGTAGTGGATACAATTATTTGGATTGGTATCTGCAGAAGCCAGGACAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAGTCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGTCTACAAACTCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 318 ATX-P-578 VL – Nucleotide GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCAGTTGCCGGGCCAGTCAGAGTGTTAATAGCTGGTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATAAGGCGTCTAATTTAGAAGGTGGGGTCCCATCAAGTTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAATATGATACTTCTTGGACGTTCGGCCAAGGGACCAAGGTGGAGATCAAA 319 ATX-P-569 VL - Nucleotide GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGCGTCACCATCACTTGCCGGGCCAGTCAGAATATTATTACCTGGTTGGCTTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAGTAGTTATTCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 320 ATX-P-576 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGACGAGTCAGGGTATTAGAAACTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAACTGGGGGCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACAGTTTCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 321 ATX-P-588 VL - Nucleotide GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 322 ATX-P-596 VL - Nucleotide GACATCGTGATGACTCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAGTATGGTAGCTCACCCATGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 323 ATX-P-600 VL - Nucleotide GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAATGTTAGGGGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATATATGGTGCATCCAACAGGGCCACTGACATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCGGCCTGGAGCCTGAAGATTTTGTAGTGTATTACTGTCAGCAGTATGGTAGTTCGTACACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA 324 ATX-P-571 VH QVQLQESGPGLVKPSGTLSLTCAVSGGSISSRNWWSWVRQPPGKGLEWIGEIYHGGTTNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCARGGLRLGELSPNAFDIWGQGTMVTVSS 325 ATX-P-577 VH QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWTWVRQPPGKGLEWIGETYHDGSTNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCLEFYFDYWGQGTLVTVSS 326 ATX-P-579 VH QVQLQESGPGLVKPSGTLSLTCAVSGASISTSNWWTWVRQPPGKGLEWIGEIYHDGSTNYSPSLQSRVTISVDKSKNQFSLTLTSVTAADTAIYYCGDFYIDVWGNGTTVTVSS 327 ATX-P-580 VH QVQLQESGPGLVKPSGTLSLTCAVSGGSISTSDWWTWVRQPPGKGLEWIGEIYHSGSTNYNPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCADWYFDLWGRGTLVTVSS 328 ATX-P-582 VH QVQLQESGPGLVKPSGTLSLTCAVSGGSISISKWWSWVRQPPGKGLEWIGEIYHTGSTNYHPSLKSRVTISVDKSKNQFYLKLNSVTAADTAVYYCARDELRLGELSPSLDIWGQGTMVTVSS 329 ATX-P-598 VH QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQSPGKGLEWIGEIYHSGTTNYNPSLKSRVTISVDKSKNQFSLKLSSATAADTAVYYCARDRLRLGESSSDVFDIWGQGTMVTVSS 330 ATX-P-603 VH QVQLQESGPGLVKPSGTLSLTCAVSGGSISGSHWWSWFRQPPGKGLEWIGEIYHTGSTNKNPSLKSRVTISLDKSKNQFSLRLRSVTDADTAVYYCARDQYTGSPRDAFDIWGQGTMVTVSS 331 ATX-P-608 VH QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQSPGKGLEWIGEIYHTGSTNKKPSLKSRVIISVDKSKNQFSLKLISVNAADTAIYYCARDREGGTTEAFDIWGQGTMVTVSS 332 ATX-P-609 VH QVQLQESGPGLVKPSGTLSLTCAVSGGSISSSNWWSWVRQPPGKGLEWIGEIYHSGSTNYNPSLKSRVTISVDKSKNQFSLKLRSVTAADTAVYYCARDQLSSGPTDAFDIWGQGTMVTVSS 333 ATX-P-563 VH QVQLQESGPGLMKPSETLSLTCTVSGGSISSHYWSWIRQPPGKGLEWIGYIFYSGNINYNPSLKSRVTISVDTSKNQFSLKLRSVTTADTAVYYCARDRGGSYSYHFDCWGQGTLVTVSS 334 ATX-P-570 VH QVQLQESGPGLVKPSETMSLTCTVSGGSFTGYYWSWIRQPPGKGLEWIGYVHYSGGTKSNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARERYEWNSYFDYWGQGTLVTVSS 335 ATX-P-571 VH - Nucleotide CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGACCCTGTCCCTCACCTGTGCTGTCTCGGGTGGCTCCATCAGTAGTCGTAACTGGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCTATCATGGTGGGACCACCAACTACAACCCGTCCCTTAAGAGTCGAGTCACCATATCAGTAGACAAGTCCAAGAACCAATTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGGGGGATTACGTTTGGGGGAGTTATCGCCTAATGCTTTTGATATCTGGGGACAAGGGACAATGGTCACCGTCTCTTCA 336 ATX-P-577 VH – Nucleotide CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACTGGTGGACTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAACCTATCATGATGGGAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATTTCAGTAGACAAGTCCAAGAACCAATTCTCCCTGAAACTGAGTTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGTTTGGAATTCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 337 ATX-P-579 VH – Nucleotide CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGACCCTGTCCCTCACCTGCGCTGTGTCTGGTGCCTCCATCAGCACAAGTAATTGGTGGACTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGTGAAATCTATCATGATGGGAGCACCAACTACAGCCCGTCCCTCCAGAGTCGAGTCACCATATCAGTAGACAAGTCCAAGAACCAGTTCTCCCTGACGCTGACCTCTGTGACCGCCGCGGACACGGCCATTTATTATTGTGGTGACTTCTACATAGACGTCTGGGGCAACGGGACCACGGTCACCGTCTCCTCA 338 ATX-P-580 VH – Nucleotide CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCACTAGTGACTGGTGGACTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACAAATCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGGACTGGTACTTCGATCTCTGGGGCCGTGGCACCCTGGTCACTGTCTCCTCA 339 ATX-P-582 VH – Nucleotide CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGACCCTGTCCCTCACCTGCGCTGTGTCTGGTGGCTCCATCAGCATTAGTAAATGGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGGAAATCTATCATACTGGGAGCACCAACTACCACCCGTCCCTCAAGAGCCGAGTCACCATATCAGTAGACAAGTCCAAGAACCAATTCTACCTGAAGCTGAACTCTGTGACCGCCGCGGACACGGCCGTATATTACTGTGCGAGAGATGAATTACGGTTGGGGGAGTTATCGCCCTCTCTTGATATCTGGGGACAAGGGACAATGGTCACCGTCTCTTCA 340 ATX-P-598 VH - Nucleotide CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACTGGTGGAGTTGGGTCCGCCAGTCCCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCTATCATAGTGGGACCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACAAGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGCGACCGCCGCGGACACGGCCGTGTATTATTGTGCGAGAGATAGATTACGTTTGGGGGAGTCATCGTCCGATGTTTTTGATATCTGGGGACAAGGGACAATGGTCACCGTCTCTTCA 341 ATX-P-603 VH - Nucleotide CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCGGTAGTCACTGGTGGAGTTGGTTCCGCCAGCCCCCAGGAAAGGGGCTGGAGTGGATTGGGGAAATCTATCATACTGGGAGCACCAACAAAAACCCGTCCCTCAAGAGTCGAGTCACTATCTCATTAGACAAGTCCAAGAATCAGTTCTCCCTGAGGCTGAGGTCTGTGACCGACGCGGACACGGCCGTGTATTACTGTGCGAGAGATCAGTATACTGGGAGCCCAAGGGATGCTTTTGATATCTGGGGACAAGGGACAATGGTCACCGTCTCCTCA 342 ATX-P-608 VH - Nucleotide CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACTGGTGGAGTTGGGTCCGCCAGTCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCTATCATACTGGGAGCACCAACAAAAAACCGTCCCTCAAGAGTCGAGTCATCATATCAGTAGACAAGTCCAAGAACCAGTTCTCCCTGAAACTGATCTCTGTGAACGCCGCGGACACGGCCATATATTACTGTGCGAGAGATCGGGAAGGGGGAACTACTGAAGCTTTTGATATCTGGGGACAAGGGACAATGGTCACCGTCTCTTCA 343 ATX-P-609 VH - Nucleotide CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACTGGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACAAGTCCAAGAACCAGTTCTCCCTGAAGCTGAGGTCTGTGACCGCCGCGGACACGGCCGTTTATTACTGTGCGAGAGATCAACTAAGTAGCGGACCTACGGATGCTTTTGATATCTGGGGACAAGGGACAATGGTCACCGTCTCTTCA 344 ATX-P-563 VH - Nucleotide CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGATGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTCACTACTGGAGCTGGATCCGGCAACCCCCAGGGAAGGGACTGGAGTGGATTGGATATATCTTTTACAGTGGGAACATAAATTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGGTCTGTGACCACTGCGGACACGGCCGTATATTACTGTGCGAGAGATCGAGGTGGGAGCTATTCGTACCACTTTGACTGCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 345 ATX-P-570 VH - Nucleotide CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACTATGTCCCTCACCTGCACTGTCTCTGGTGGCTCCTTCACTGGATACTACTGGAGTTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGATATGTCCATTACAGTGGGGGCACCAAAAGCAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTTTCCCTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGAGAGAGGTATGAGTGGAACTCCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 346 ATX-P-571 VL DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKVLIYAASSLQSGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQETYSVPLTFGGGTKVEIK 347 ATX-P-577 VL DIQMTQSPSSLSASVGDRVTITCRASQDIRNDLGWYQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFASYYCLQYNNYPFTLGPGTKVDIK 348 ATX-P-579 VL DIQMTQSPSSLSASVGDRVTITCRASQGIRKDLGWYQQKPGKAPKRLIYTASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQYNNYPFTFGPGTKVDIK 349 ATX-P-580 VL DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSGTEFTLAISSLQPEDFATYYCLHFNSYPFTFGPGTKVDIK 350 ATX-P-582 VL DIQMTQSPSSLSASVGDRVTITCRASQNINNYLNWFRQKPGKAPKLLIFAASSLQSGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK 351 ATX-P-598 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPELLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDMAVYYCQQFYNTPYTFGQGTKVDIK 352 ATX-P-603 VL EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGNSPLTFGGGTKVEIK 353 ATX-P-608 VL EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPVRFSGSGSGTQFTLTISSLQSEDFAVYYCQQYDNWRTFGQGTRLEIK 354 ATX-P-609 VL EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPVRFSGSGSGTQFTLTISSLQSEDFAVYYCQQYDNWRTFGQGTKLEIK 355 ATX-P-563 VL DIQMTQSPSSVSASVGDRVTITCRASQSFAGWLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPLTFGGGTKVEIK 356 ATX-P-570 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYHQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSSPRTFGQGTKVEIK 357 ATX-P-571 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGGTCCTGATCTATGCTGCATCCAGTTTGCAGAGTGGGATCCCATCACGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAAGAGACTTACAGTGTTCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA 358 ATX-P-577 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCTAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTCGCAAGTTATTACTGTCTACAGTATAATAATTATCCATTCACTCTCGGCCCTGGGACCAAAGTGGATATCAAA 359 ATX-P-579 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAAAAGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATACTGCATCCACTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGTATAATAATTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 360 ATX-P-580 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCTTCTGTCGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCGCAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACACTTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 361 ATX-P-582 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAACATTAACAACTATTTAAATTGGTTCCGGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTTGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGATTCAGTGGCAGTGAATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAGGATTTTGCGACTTACTACTGTCAACAGAGTTACAGTACCCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA 362 ATX-P-598 VL - Nucleotide GACATCGTGATGACTCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTGAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATATGGCAGTTTATTACTGTCAACAATTTTATAATACTCCGTACACTTTTGGCCAGGGGACCAAAGTGGATATCAAA 363 ATX-P-603 VL – Nucleotide GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCATTATGGTAACTCACCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA 364 ATX-P-608 VL – Nucleotide GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGTCAGGTTCAGTGGCAGTGGGTCTGGGACACAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTATTGTCAGCAATATGATAACTGGCGGACGTTCGGCCAAGGGACACGACTGGAGATTAAA 365 ATX-P-609 VL - Nucleotide GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGTCAGGTTCAGTGGCAGTGGGTCTGGGACACAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTATTGTCAGCAATATGATAACTGGCGGACGTTCGGCCAAGGGACCAAGCTGGAAATCAAA 366 ATX-P-563 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTCGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGAGTTTTGCCGGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATATATGCTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACAGTTTCCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA 367 ATX-P-570 VL - Nucleotide GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGTCAGAGTGTTTTATACAGCTCCAACAATAAGAATTACTTAGCTTGGTACCACCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATACTATAGTAGTCCTCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 368 ATX-P-560 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNTAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLSSVTPQDTAIYYCASDNWNNGGPGFDPWGQGTLVTVSS 369 ATX-P-561 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYNGYAVSMKSRITINPDTSKNQFSLQLNSVTPEDTAMYYCAREGVGATTGFDYWGQGTLVTVSS 370 ATX-P-562 VH QVQLQQSGPGLVKSSQTLSLTCAISGDTVSSNSAAWNWIRQSPSRGLEWLGRTFYRSRWSAAYAASVSSRITINPDTSKNQFSLQLTSVTPADTAVYYCAREGVGSSTGFDYWGQGTLVTVSS 371 ATX-P-566 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWFNNYSVSVKSRIAINPDTSKNQFSLQLNSVTPEDTAVYYCARDLGELLDWYFDLWGRGTLVTVSA 372 ATX-P-572 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGMTYYRSKWYSVFAVSVKSRITINTDTSKNQFSLQLNSVTPEDTAVYYCAREGGIVGATPFDYWGQGTLVTVSS 373 ATX-P-573 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKLYSDYAVSVKSRITINPDTSRNQFSLQLNSVTPEDTAVYYCAREGGYTYGYDYWGQGTLVTVSS 374 ATX-P-581 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNNAAWNWIRQSPSRGLEWLGRTYYRSKWYNAYAVSVKSRIIINPDTSRNQFSLQLNSVTPEDTAVYYCAREGGYIYGLDQWGQGTLVTVSS 375 ATX-P-587 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRSKWYNYYALSVKSRITINPDTSKNQFSLHLNSVTPEDTAVYYCARDGDYYLPSPFDLWGHGTMVTVSS 376 ATX-P-592 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYSDYPLSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARDSGIVETTPFDYWGQGTLVTVSS 377 ATX-P-594 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSASWNWIRQSPSRGLEWLGTTYYRSKWFNVYAVSVKSRITINPDTSKNQFSLHLNSVTPEDTAIYFCTRDRGDLLHWYFDLWGRGTLVTVSS 378 ATX-P-595 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWFNDYALSVKSRITINPDTSKNQFSLHLNSVTPEDTAVYYCAREPGIVAPGPFDYWGQGTLVTVSS 379 ATX-P-604 VH QVQLQQSGPGLVKPTQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWFNGYAVSVKSRITINPDASKNQFSLHLKSVTDEDTAVYYCATDRGELLHWYFDLWGRGTLVTVSS 380 ATX-P-610 VH QVQLQQSGPGLVKSSQTLSITCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYALSVKSRIIIKSDTSKNQFSLQLNSVTPEDTAVYYCAREPGIAAPGPFDYWGQGSLVTVSS 381 ATX-P-560 VH - Nucleotide CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATTTCCGGGGACAGTGTCTCTAGCAACACTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCTGCAGTTGAGCTCTGTGACTCCCCAGGACACGGCTATATATTACTGTGCGAGCGATAACTGGAACAACGGAGGCCCTGGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 382 ATX-P-561 VH - Nucleotide CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAAGTGGTATAATGGTTATGCAGTCTCTATGAAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTATGTATTATTGTGCAAGAGAGGGAGTGGGAGCTACTACAGGCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 383 ATX-P-562 VH - Nucleotide CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGTCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACACTGTCTCTAGTAATAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATTCTATAGGTCCAGGTGGTCTGCTGCTTATGCAGCGTCTGTGAGTAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCTGCAGCTGACCTCTGTGACTCCCGCGGACACGGCTGTGTATTACTGTGCAAGAGAGGGAGTAGGATCTTCTACAGGCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 384 ATX-P-566 VH - Nucleotide CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAAGTGGTTTAATAATTATTCAGTTTCTGTGAAAAGTCGAATAGCCATTAACCCAGACACATCCAAGAACCAGTTCTCCCTTCAACTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGATCTGGGGGAGTTACTTGACTGGTACTTCGATCTCTGGGGCCGTGGCACCCTGGTCACTGTCTCCGCA 385 ATX-P-572 VH – Nucleotide CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAATGACATACTACAGGTCCAAGTGGTATAGTGTTTTTGCAGTATCTGTGAAAAGTCGAATAACCATCAATACAGACACATCCAAGAACCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGAGGGGGGTATAGTGGGAGCCACCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA 386 ATX-P-573 VH – Nucleotide CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGCAGGACATACTACAGGTCCAAGTTGTATAGTGATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCAGACACATCCAGGAACCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGAGGGGGGATACACCTATGGTTATGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 387 ATX-P-581 VH - Nucleotide CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAATGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACGTACTACAGGTCCAAGTGGTATAATGCTTATGCAGTTTCTGTGAAAAGTCGAATTATCATCAATCCAGACACATCCAGGAACCAGTTCTCCCTGCAACTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGAGGGTGGATACATCTATGGTCTTGACCAATGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 388 ATX-P-587 VH - Nucleotide CAGGTGCAGCTGCAGCAGTCGGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAAGACATACTACAGGTCCAAGTGGTATAATTATTATGCACTATCTGTGAAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCTGCACCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGACGGTGACTACTACCTTCCCTCTCCTTTTGATCTCTGGGGCCACGGGACAATGGTCACCGTCTCCTCA 389 ATX-P-592 VH – Nucleotide CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAAGTGGTATAGTGATTATCCACTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACATCCAAGAACCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGACTCCGGTATAGTTGAAACCACGCCCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 390 ATX-P-594 VH – Nucleotide CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGTAACAGTGCTTCTTGGAACTGGATCAGGCAGTCCCCTTCGAGAGGCCTTGAGTGGCTGGGAACGACATACTACAGGTCCAAGTGGTTTAATGTTTATGCAGTCTCTGTGAAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAATTCTCCCTGCACCTGAACTCTGTGACTCCCGAGGACACGGCTATATATTTCTGTACAAGAGATCGGGGGGACCTACTCCACTGGTACTTCGATCTCTGGGGCCGTGGCACCCTGGTCACTGTCTCCTCA 391 ATX-P-595 VH – Nucleotide CAGGTACAGCTGCAGCAGTCGGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAAGTGGTTTAATGATTATGCACTATCTGTGAAAAGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCTGCACCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGAACCTGGTATAGTAGCACCTGGCCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 392 ATX-P-604 VH – Nucleotide CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCACGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCATGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGGAGGACATACTACAGGTCCAAGTGGTTTAATGGTTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACGCATCCAAGAACCAGTTCTCCCTGCACTTGAAGTCTGTGACTGACGAGGACACGGCTGTATATTACTGTGCAACAGATCGGGGGGAACTCCTCCACTGGTACTTCGATCTCTGGGGCCGTGGCACCCTGGTCACCGTCTCTTCA 393 ATX-P-610 VH - Nucleotide CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGTCCTCGCAGACCCTCTCAATCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCACTATCTGTGAAAAGTCGAATAATCATCAAGTCAGACACATCCAAGAACCAGTTCTCCCTGCAGTTGAACTCTGTGACTCCCGAGGACACGGCTGTGTACTACTGTGCAAGAGAACCGGGTATAGCAGCACCTGGTCCATTTGACTACTGGGGCCAGGGATCCCTGGTCACCGTCTCCTCA 394 ATX-P-560 VL DIQMTQSPSSVSTSVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLISAASSLQSGVPSRFSGSGSGTDFTLTISTLQPEDFASYYCQQANSFPPTFGQGTRVEIK 395 ATX-P-561 VL DIQMTQSPSSLSASVGDRVTITCRASQGISSWLTWYQQKPGKAPKLLIYAASSLQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPPTFGQGTKVEIK 396 ATX-P-562 VL DIQMTQSPSSVSASIGDRVTITCRASKGISIWLAWYQQKPGKAPKVLISAASSLQSGAPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPPTFGQGTKVEIK 397 ATX-P-566 VL EIVLTQSPGTLSLSPGDRATLSCRASQSVRNSYVAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFSLTIGRLEPEDFVVYYCQQYGNSPLTFGGGTKVEIK 398 ATX-P-572 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASPRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSIPRTFGQGTKVEIK 399 ATX-P-573 VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKVLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPPTFGPGTKVDIK 400 ATX-P-581 VL DIQMTQSPSSVSASVGDRVTITCRASQGVNNWLAWYQQKPGKAPKLLIHAASSLLSGVPSRFSGSGSGTDFTLTITSLQPEDFATYYCQQANSFPITFGQGTRLEIK 401 ATX-P-587 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPYTFGQGTKLEIK 402 ATX-P-592 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASNRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPYTFGQGTKLEIK 403 ATX-P-594 VL EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQSPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGRSVTFGGGTKLEIK 404 ATX-P-595 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPYTFGQGTKLEIK 405 ATX-P-604 VL EIVLTQSPDTLSLSPGERATLSCRASQTIRSSYLAWYQLKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLSISRLEPEDFAVYYCQQYGRSIIFGGGTKVEIK 406 ATX-P-610 VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNYRTPITFGQGTRLEIK 407 ATX-P-581 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTTGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTCTGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCACCCTGCAGCCTGAAGACTTTGCATCTTACTATTGTCAACAGGCTAACAGTTTCCCTCCGACGTTCGGCCAAGGGACCAGGGTGGAAATCAAA 408 ATX-P-561 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCTTCCCTGTCTGCATCTGTCGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAACCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAGGTGGGGTCCCATCAAGATTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACAGTTTCCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 409 ATX-P-573 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTATAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTAAGGGAATTAGCATCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGGTCCTGATCTCTGCTGCATCCAGTTTGCAAAGTGGGGCCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACAGTTTCCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAGATCAAA 410 ATX-P-610 VL - Nucleotide GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGACAGAGCCACCCTCTCATGCAGGGCCAGTCAGAGTGTTAGGAACAGTTACGTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCAGTCTCACCATCGGCAGACTGGAGCCTGAGGATTTTGTAGTGTATTATTGTCAGCAATACGGTAACTCACCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA 411 ATX-P-560 VL - Nucleotide GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCTGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTCCCCGGGAATCCGGGGTCCCTGACCGGTTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTATTGTCAGCAATATTATAGTATTCCTCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA 412 ATX-P-562 VL - Nucleotide GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGGTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACAGTTTCCCTCCCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 413 ATX-P-566 VL - Nucleotide GACATCCAGATGACTCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTGTTAACAACTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATGCTGCATCCAGTTTGCTAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACGCTCACCATCACCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACAGTTTCCCCATCACCTTCGGCCAAGGGACACGACTGGAAATTAAA 414 ATX-P-604 VL – Nucleotide GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTACTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 415 ATX-P-594 VL – Nucleotide GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTAACCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCTCCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTACTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA 416 ATX-P-572 VL – Nucleotide GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAGAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGTCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAGGATTTTGCAGTATATTACTGTCAGCAGTATGGTAGGTCAGTCACTTTCGGCGGAGGGACCAAGCTGGAAATCAAA 417 ATX-P-587 VL – Nucleotide GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTACTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAAATCAAA 418 ATX-P-592 VL – Nucleotide GAAATAGTGCTGACTCAGTCTCCAGACACCCTATCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGACTATTAGGAGCAGCTACTTAGCCTGGTACCAGCTGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCTCCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAACAGTATGGCCGCTCAATCATTTTCGGCGGAGGGACCAAAGTGGAAATCAAA 419 ATX-P-595 VL – Nucleotide GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTACTGTCAACAGAATTACAGAACCCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA

[0225] Table 5: Anti-CFHR4 antibody (HC IgG1 Fc and LCκ sequences)

[0226] SEQ IDNO: Antibody name: Descriptor: Sequence: 420 ATX-P-583 HC IgG1 Fc QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYGISWVRQAPGQGLEWMGWISAYSGNTHYAQSLQDRVTMTTDTSTSTAYMEVRSLRSDDTAVYYCAKDEGYCSSTGCLNLFDPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 421 ATX-P-591 HC IgG1 Fc QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAIYYCTRDLRGTAFDYWGQGTPVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 422 ATX-P-602 HC IgG1 Fc QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNYAKKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGDTIFRLVTPLDYWGQGTLVTSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 423 ATX-P-597 HC IgG1 Fc QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYMQWVRQAPGQGLEWLGIIDPSGGSTTYAQKFQGRVTMTRDTSTSTVHMELRSLRSEDTAVYYCARDEGTDRPGWGYWGQGTLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 424 ATX-P-601 HC IgG1 Fc QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTNYAQKFQGRLTMTRDTSTNTVYMELSSLRSEDTAVYYCATDQSGGMDVWGKGTTTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 425 ATX-P-607 HC IgG1 Fc QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTNTVYMELSSLRSEDTAVYYCARDPEYSSAFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 426 ATX-P-583 HC IgG1 Fc - Nucleotide CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCACCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAGTGGTAACACACACTATGCACAGAGCCTCCAGGACAGAGTCACCATGACCACAGACACATCCACGAGTACAGCCTACATGGAGGTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAAAGATGAGGGATATTGTAGTAGTACCGGCTGCTTAAACTTGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCCCGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTGAAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCTGACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGTATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAGACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAAACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCCCGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAGCCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGTGGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTGATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTACGCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTGGCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGGCCCCAATCGAGAAAACCATTTCCAAGGCCAAAGGTCAACCAAGAGAACCCCAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGTATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTGAATGGGAATCGAACGGTCAGCCGGAGAATAATTATAAAACAACGCCACCCGTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGATAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT 427 ATX-P-591 HC IgG1 Fc - Nucleotide CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGCTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACTGCCATTTATTACTGTACGAGAGATCTACGTGGAACTGCCTTTGACTACTGGGGCCAGGGAACCCCGGTCACTGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCCCGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTGAAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCTGACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGTATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAGACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAAACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCCCGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAGCCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGTGGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTGATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTACGCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTGGCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGGCCCCAATCGAGAAAACCATTTCCAAGGCCAAAGGTCAACCAAGAGAACCCCAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGTATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTGAATGGGAATCGAACGGTCAGCCGGAGAATAATTATAAAACAACGCCACCCGTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGATAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT 428 ATX-P-602 HC IgG1 Fc - Nucleotide CAGGTGCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCAAAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGTTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGGGGATACGATTTTTCGACTGGTTACCCCTCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCCCGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTGAAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCTGACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGTATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAGACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAAACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCCCGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAGCCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGTGGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTGATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTACGCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTGGCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGGCCCCAATCGAGAAAACCATTTCCAAGGCCAAAGGTCAACCAAGAGAACCCCAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGTATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTGAATGGGAATCGAACGGTCAGCCGGAGAATAATTATAAAACAACGCCACCCGTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGATAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT 429 ATX-P-597 HC IgG1 Fc - Nucleotide CAGGTGCAGCTGGTGCAATCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACACCTTCACCAACTACTATATGCAGTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGCTGGGAATAATCGACCCTAGTGGTGGTAGCACAACCTATGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCCACATGGAGCTGAGAAGTCTGAGATCTGAGGACACGGCCGTCTATTATTGCGCGAGAGATGAGGGAACAGATCGTCCCGGGTGGGGCTACTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCCCGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTGAAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCTGACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGTATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAGACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAAACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCCCGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAGCCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGTGGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTGATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTACGCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTGGCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGGCCCCAATCGAGAAAACCATTTCCAAGGCCAAAGGTCAACCAAGAGAACCCCAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGTATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTGAATGGGAATCGAACGGTCAGCCGGAGAATAATTATAAAACAACGCCACCCGTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGATAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT 430 ATX-P-601 HC IgG1 Fc - Nucleotide CAGGTGCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACACCTTCACCAGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAATAATCAACCCTAGTGGTGGTAGCACAAACTACGCACAGAAGTTCCAGGGCAGACTCACCATGACCAGGGACACGTCCACGAACACAGTCTACATGGAACTGAGTAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGACAGATCAAAGTGGGGGGATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCCCGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTGAAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCTGACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGTATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAGACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAAACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCCCGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAGCCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGTGGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTGATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTACGCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTGGCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGGCCCCAATCGAGAAAACCATTTCCAAGGCCAAAGGTCAACCAAGAGAACCCCAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGTATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTGAATGGGAATCGAACGGTCAGCCGGAGAATAATTATAAAACAACGCCACCCGTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGATAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT 431 ATX-P-607 HC IgG1 Fc - Nucleotide CAGGTGCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACACCTTCACCAGTTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAATAATCAACCCTAGTGGTGGTAGCACAAGCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCAACGAACACAGTCTACATGGAGCTGAGCAGCCTTCGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGATCCCGAGTATAGCAGTGCTTTTGATATCTGGGGACAAGGGACAATGGTCACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCCCGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTGAAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCTGACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGTATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAGACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAAACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCCCGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAGCCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGTGGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTGATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTACGCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTGGCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGGCCCCAATCGAGAAAACCATTTCCAAGGCCAAAGGTCAACCAAGAGAACCCCAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGTATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTGAATGGGAATCGAACGGTCAGCCGGAGAATAATTATAAAACAACGCCACCCGTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGATAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT 432 ATX-P-583 LC κ DIQMTQSPSSLSASVGDRVTITCRASQNIGSYLNWYQQKPGNAPKLLIYATSTLQSGVPSRFSGSGSGTDFTLIISSLHPEDFTVYYCQQSFIIPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 433 ATX-P-591 LC κ DIQMTQSPSSLSASVGDRVTITCRASQSINTYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYSCQHSFTTPFTFGPGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 434 ATX-P-602 LC κ EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTQFTLTISSLQSEDFAVYYCQQYGSSPWTFGQGTKVDI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 435 ATX-P-597 LC κ DIQMTQSPSSLSASIGDRVTITCRASQSISSYLDWYQRKSGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVDIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 436 ATX-P-601 LC κ DIQMTQSPSSLSASVGDRVTITCRASQSINIYLNWYQQKPEKDPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISNLQPEDFATYYCQQSYSTPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 437 ATX-P-607 LC κ DIQMTQSPSSLSASVGDRGTITCRASQSIRSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYRTPVTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 438 ATX-P-583 LC κ - Nucleotide GACATCCAGATGACCCAGTCTCCGTCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAACATTGGCAGTTATTTAAATTGGTATCAGCAGAAACCAGGGAATGCCCCTAAACTCCTGATCTATGCTACATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCATCATCAGCAGTCTGCACCCTGAAGATTTTACAGTTTATTACTGTCAACAGAGTTTCATTATCCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCGGGAAATTCACAGGAAAGTGTTACGGAGCAGGATTCTAAAGATTCCACATATTCACTCAGCTCCACCCTTACACTGAGCAAAGCCGACTATGAAAAACATAAAGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT 439 ATX-P-591 LC κ - Nucleotide GACATCCAGATGACTCAGTCTCCATCCTCCCTGTCTGCATCTGTTGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAACACCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTCCTGTCAACATAGTTTCACTACCCCATTCACTTTCGGCCCTGGGACCAAGCTGGAAATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCGGGAAATTCACAGGAAAGTGTTACGGAGCAGGATTCTAAAGATTCCACATATTCACTCAGCTCCACCCTTACACTGAGCAAAGCCGACTATGAAAAACATAAAGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT 440 ATX-P-602 LC κ - Nucleotide GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGTAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACACAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATGGTAGCTCACCGTGGACGTTCGGCCAAGGGACCAAAGTGGATATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCGGGAAATTCACAGGAAAGTGTTACGGAGCAGGATTCTAAAGATTCCACATATTCACTCAGCTCCACCCTTACACTGAGCAAAGCCGACTATGAAAAACATAAAGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT 441 ATX-P-597 LC κ – Nucleotide GACATCCAGATGACCCAGTCT...

Claims

1. An antibody or antigen-binding fragment thereof, which specifically binds to human complement factor H-related (CFHR) 4, optionally wherein the human CFHR4 is a CFHR4b variant (CFHR4b), which is optionally a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:

580.

2. The antibody or fragment of claim 1, wherein the antibody or fragment exhibits any one or more of the following functional characteristics: a. reducing complement activation and / or attenuating complement component 3 (C3) convertase activity relative to the absence of the antibody or fragment, which is optionally measured in an in vitro C3 convertase assembly assay; and / or b. cross-reacts with at least one of cynomolgus monkey CFHR4b protein (cCFHR4b), human CFHR4a variant (CFHR4a), human complement factor H-related protein 3 (CFHR3) and / or complement factor H-related protein 1 (CFHL1); and / or c. does not cross-react with at least one of cynomolgus monkey CFHR4b protein (cCFHR4b), human CFHR4a variant (CFHR4a), human complement factor H-related protein 3 (CFHR3) and / or complement factor H-related protein 1 (CFHL1); and / or d. With a K of about 100 nM or less D binds to human CFHR4; and / or e. binds to the same epitope on human CFHR4 as an antibody comprising the VH and VL sequences of any of the exemplary antibodies whose sequences are provided in Table 6; and / or f. Competing for binding to human CFHR4 with an antibody comprising the VH and VL sequences of any of the exemplary antibodies whose sequences are provided in Table 6.

3. The antibody or fragment according to any one of the preceding claims, which is monoclonal, optionally recombinant.

4. The antibody or fragment of any one of the preceding claims which is human, humanized or chimeric.

5. The antibody or fragment of any of the preceding claims, which is a full length antibody, a single chain antibody, a single chain variable fragment (scFv), a variable fragment (Fv), a fragment antigen binding region (Fab), Fab-C, Fab'-SH, (Fab')2, a single domain antibody (sdAb), a VHH antibody, a nanobody, a camelid-derived single domain antibody, a shark IgNAR-derived single domain antibody fragment (VNAR), a diabody, a triabody, anticalin or an aptamer, optionally wherein the antibody is a full length antibody comprising an Fc region such as a human IgG1, IgG2, IgG3 or IgG4 region.

6. The antibody or fragment of any of the preceding claims, conjugated to at least one other moiety, optionally selected from: a. an antigen binding portion, such as an antibody or antigen binding fragment thereof, which antigen binding portion is capable of specifically binding to a target other than human CFHR4, preferably wherein the target is expressed in the human eye; b. Therapeutic or cytotoxic moiety; c. Detection part; d. Purification part; e. A half-life extending moiety, optionally a polypeptide of at least 20 amino acids in length and comprising any combination of G, A, ST, E and P residues, conjugated to the C-terminus or N-terminus of the antibody.

7. The antibody or fragment of any one of the preceding claims, which is a polypeptide comprising: a. one, two or all three HCDRs of any one of the exemplary antibodies, and optionally further comprising one, two or all three corresponding LCDRs of said exemplary antibodies, the sequences of said exemplary antibodies being provided in Table 6; and / or b. a VH sequence having at least 90% identity to the VH sequence of any one of the exemplary antibodies, and optionally further comprising a VL sequence having at least 90% identity to the corresponding VL sequence of the exemplary antibodies, the sequences of the exemplary antibodies being provided in Table 6, preferably wherein no variation in the HCDR or LCDR is allowed; and / or c. all six CDRs of any of the exemplary antibodies whose sequences are provided in Table 6; and / or d. the VH and VL sequences of any of the exemplary antibodies whose sequences are provided in Table 6; and / or e. A full-length heavy chain (VH + constant region) sequence of any one of the exemplary antibodies, and optionally comprising the corresponding full-length light chain (VL + constant region) sequence of the exemplary antibodies, the sequences of the exemplary antibodies are provided in Table 6.

8. A polynucleotide encoding an antibody or fragment as described in any of the preceding claims, optionally wherein the polynucleotide comprises or consists of a nucleic acid sequence that is at least 70%, 80%, 90% or 100% identical to the nucleic acid sequence of any of the exemplary antibodies, the sequences of which are provided in Table 6.

9. An expression vector comprising the polynucleotide of claim 8, wherein the expression vector is optionally an adeno-associated virus (AAV) vector, a lentivirus (LV) vector, a herpes simplex virus (HSV) vector or a retrovirus vector.

10. A pharmaceutical composition comprising the antibody or fragment, polynucleotide or vector according to any one of the preceding claims, and optionally: a. at least one pharmaceutically acceptable carrier, diluent or preservative; and / or b. at least one additional active ingredient.

11. The pharmaceutical composition of claim 10, which is suitable for ocular administration to a subject, optionally delivered by use of a conjunctival insert, a contact lens, a gel, nanoparticles, a mucoadhesive polymer, an ointment, a solution, a suspension, eye drops and / or an implant, preferably by injection into the vitreous humor.

12. The antibody or fragment of any one of claims 1 to 7, the polynucleotide of claim 8, the vector of claim 9 or the composition of claim 10 or 11 for use as a medicament, optionally for use in a method of treating an eye disease in a subject.

13. The antibody, fragment, polynucleotide, carrier or composition for use as claimed in claim 12, wherein the disease is characterized by increased activation of the complement system, particularly the alternative pathway, and particularly in the eye of the experimenter, such as in drusen or retinal pigment epithelial (RPE) cells of the experimenter.

14. The antibody, fragment, polynucleotide, vector or composition for use of claim 12 or 13, wherein the method comprises ocular administration of the antibody, preferably by injection into the vitreous humor, and wherein the administration preferably alleviates at least one symptom of the subject selected from the group consisting of visual distortion, decreased central vision, blurred vision and / or difficulty adapting to dim light.

15. The antibody, fragment, polynucleotide, carrier or composition for use as described in any one of claims 12 to 14, wherein the disease is age-related macular degeneration (AMD), optionally wherein the AMD is dry AMD, which may be in early, middle or late stages (the latter also referred to as geographic atrophy, GA).

16. An antibody or antigen-binding fragment thereof against a complement factor H-related 4 (CFHR4) peptide, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and the VL comprises complementarity determining regions (CDRs) LCDR1, LCDR2 and LCDR3, wherein: The HCDR1 comprises one of the following amino acid sequences: (a) X1YX2X3X4 (SEQ ID NO: 1), wherein X1 is S, T, G or N; X2 is G or Y; X3 is I or M; X4 is S, H or Q; (b) X1YX2X3X4 (SEQ ID NO: 21), wherein X1 is S, T, R or D; X2 is T, V, A, G, S or E; X3 is M or I; X4 is N, S or H; (c) X1X2X3WX4X5 (SEQ ID NO: 53), wherein X1 is T, S, G or I; X2 is S, R, Y or H; X3 is D, N, H, K or Y; X4 is W or S; X5 is T or S; or (d) SNX1AX2WN (SEQ ID NO: 88), wherein X1 is S, T or N; X2 is A or S; Wherein the HCDR2 comprises one of the following amino acid sequences: (a) X1IX2X3X4X5GX6TX7X8X9X 10 X 11 X 12 QX 13 (SEQ ID NO: 8), wherein X1 is W or I; X2 is S, N or D; X3 is A or P; X4 is Y, N or S; X5 is N, G or S; X6 is N, S or G; X7 is N, H, T or S; X8 is Y or N; X9 is A or Y; X 10 Q or A; X 11 K or S; X 12 L or F; X 13 is G or D; (b) X1IX2X3X4X5X6X7X8X9X 10 X 11 DX 12 VX 13 G (SEQ ID NO: 32), wherein X1 is S, V, Y, G or D; X2 is S or W; X3 is S, V, G, H or W; X4 is S, D, N or T; X5 is S or G; X6 is S or G; X7 is Y, S, T or R; X8 is T, K, I or V; X9 is Y, F, N or G; X 10 Y or H; X 11 A or V; X 12 S or P; X 13 is R, K or T; (C) X1X2X3X4X5GX6X7X8X9X 10 PLSX 11 S (SEQ ID NO: 65), wherein X1 is E or Y; X2 is I, T or V; X3 is Y, H or F; X4 is H or Y; X5 is S, D, T, G; X6 is S, T, G or N; X7 is T or I; X8 is N or K; X9 is Y, K or S; X 10 N, S, K or H; X 11 is King or Queen; or (d) X1TX2YRSX3X4X5X6X7X8X9X 10 SX 11 X 12 S (SEQ ID NO: 102), wherein X1 is R, T, M or K; X2 is Y or F; X3 is K or R; X4 is W or L; X5 is F, Y or S; X6 is N, S, D or A; X7 is N, V, G, D, Y or A; X8 is Y or F; X9 is S, A or P; X 10 V, L or A; X 11 V or M; X 12 is K or S; Wherein the HCDR3 comprises one of the following amino acid sequences: (a) SEQ ID NO: 15-20; (b) SEQ ID NO: 43-52; (c) SEQ ID NO: 77-87; or (d) SEQ ID NOs: 116-128; and wherein the LCDR1 comprises an amino acid sequence of any one of SEQ ID NOs: 130-151, SEQ ID NOs: 198-199, SEQ ID NOs: 207-215 or SEQ ID NOs: 237-243; the LCDR2 comprises an amino acid sequence of any one of SEQ ID NOs: 153-174, SEQ ID NOs: 201-202, SEQ ID NOs: 217-225 or SEQ ID NOs: 245-251; and the LCDR3 comprises an amino acid sequence of any one of SEQ ID NOs: 175-196, SEQ ID NOs: 204-205, SEQ ID NOs: 227-235 or SEQ ID NOs: 253-259.

17. An antibody or antigen-binding fragment thereof against a complement factor H-related 4 (CFHR4) peptide, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and the VL comprises complementarity determining regions (CDRs) LCDR1, LCDR2 and LCDR3, wherein: The LCDR1 comprises one of the following amino acid sequences: (a) RX1SX2X3X4X5X6X7LX8 (SEQ ID NO: 129), wherein X1 is A or T; X2 is Q or K; X3 is G, S, D or N; X4 is I, F or V; X5 is T, R, A, S, N, G or I; X6 is T, N, G, S, I, K or Y; X7 is W, D or Y; X8 is A, T, G, N or D; (b) RSSQX1LLHSX2GYNX3LD (SEQ ID NO: 197), wherein X1 is S or R; X2 is T or S; X3 is F or Y; (c) RASQX1X2X3X4X5X6X7X8A (SEQ ID NO: 206), wherein X1 is S, N or T; X2 is V or I; X3 is S or R; X4 is S, G or N; X5 is N or S; X6 is L or Y; X7 is A, L or V; or (d) SEQ ID NO: 236; Wherein the LCDR2 comprises one of the following amino acid sequences: (a) X1X2SX3LX4X5 (SEQ ID NO: 152), wherein X1 is G, A, T or K; X2 is A or T; X3 is S, T, G or N; X4 is E, Q or L; X5 is S, T or G; (b) LX1SX2RAS (SEQ ID NO: 200), wherein X1 is A or G; X2 is N or S; (c) GASX1RAT (SEQ ID NO: 216), wherein X1 is T, S or N; or (d) WASX1RES (SEQ ID NO: 244), wherein X1 is T, P or N; Wherein the LCDR3 comprises one of the following amino acid sequences: (a) SEQ ID NO: 175-196; (b) MQX1LQTPX2T (SEQ ID NO: 203), wherein X1 is A or G; X2 is Y or P; (c) QX1YX2X3X4X5X6T (SEQ ID NO: 226), wherein X1 is Q or H; X2 is D or G; X3 is N, S or R; X4 is W or S; X5 is R, P, F, Y, V or I; X6 is T, W, L or I; or (d) QQX1X2X3X4PX5X6T (SEQ ID NO: 252), wherein X1 is Y or F; X2 is G or Y; X3 is S or N; X4 is S, T or I; X5 is M, Y or R; X6 is Y or T; and wherein the HCDR1 comprises the amino acid sequence of any one of SEQ ID NOs: 2-7, SEQ ID NOs: 22-31, SEQ ID NOs: 54-64 or SEQ ID NOs: 89-101; the HCDR2 comprises the amino acid sequence of any one of SEQ ID NOs: 9-14, SEQ ID NOs: 33-42, SEQ ID NOs: 66-76 or SEQ ID NOs: 103-115; and the HCDR3 comprises the amino acid sequence of any one of SEQ ID NOs: 15-20, SEQ ID NOs: 43-52, SEQ ID NOs: 77-87 or SEQ ID NOs: 116-128.

18. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 2; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 9; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

15.

19. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 10; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

16.

20. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 11; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

17.

21. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 5; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 12; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

18.

22. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 13; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

19.

23. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

20.

24. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 22; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 33; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

43.

25. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 23; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 34; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

44.

26. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 24; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

45.

27. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 25; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 36; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

46.

28. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 26; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

47.

29. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 27; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 38; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

48.

30. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 28; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 39; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

49.

31. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 29; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 40; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

50.

32. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 30; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 41; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

51.

33. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 31; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 42; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

52.

34. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 54; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 66; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

77.

35. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 55; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 67; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

78.

36. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 56; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 68; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

79.

37. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 57; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 69; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

80.

38. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 58; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 70; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

81.

39. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 59; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 71; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

82.

40. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 60; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 72; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

83.

41. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 61; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 73; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

84.

42. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 74; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

85.

43. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 63; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 75; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

86.

44. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 64; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 76; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

87.

45. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 89; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 103; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

116.

46. ​​The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 90; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 104; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

117.

47. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 91; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 105; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

118.

48. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 92; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 106; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

119.

49. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 93; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 107; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

120.

50. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 94; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 108; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

121.

51. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 95; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 109; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

122.

52. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 96; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 110; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

123.

53. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 97; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 111; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

124.

54. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 98; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 112; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

125.

55. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 99; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 113; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

126.

56. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 100; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 114; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

127.

57. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 101; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 115; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

128.

58. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 130; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 153; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

175.

59. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 131; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 154; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

176.

60. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 132; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 155; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

177.

61. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 133; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

178.

62. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 134; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 157; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

179.

63. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 135; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 158; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

180.

64. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 136; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 159; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

181.

65. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 137; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 160; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

182.

66. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 138; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 161; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

183.

67. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 139; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 162; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

184.

68. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 140; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 163; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

185.

69. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 141; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 164; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

186.

70. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 142; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 165; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

187.

71. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 143; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 166; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

188.

72. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 144; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 167; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

189.

73. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 145; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 168; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

190.

74. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 146; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 169; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

191.

75. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 147; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 170; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

192.

76. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 148; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 171; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

193.

77. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 149; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 172; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

194.

78. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 150; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 173; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

195.

79. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 151; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 174; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

196.

80. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 198; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 201; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

204.

81. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 199; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 202; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

205.

82. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 207; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 217; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

227.

83. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 208; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 218; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

228.

84. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 209; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 219; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

229.

85. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 210; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 220; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

230.

86. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 211; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 221; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

231.

87. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 212; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 222; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

232.

88. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 213; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 223; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

233.

89. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 214; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 224; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

234.

90. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 215; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 225; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

235.

91. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 237; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 245; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

253.

92. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 238; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 246; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

254.

93. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 239; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 247; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

255.

94. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 240; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 248; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

256.

95. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 241; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 249; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

257.

96. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 242; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 250; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

258.

97. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 243; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 251; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

259.

98. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to any of: (a) SEQ ID NO: 260-265; (b) SEQ ID NO: 284-293; (c) SEQ ID NO: 324-334; or (d) SEQ ID NOs: 368-380.

99. The antibody of claim 16 or claim 17, wherein the VL comprises an amino acid sequence at least 90% identical to any of: (a) SEQ ID NO: 272-277; (b) SEQ ID NOs: 304-313; (c) SEQ ID NOs: 346-356; or (d) SEQ ID NOs: 394-406.

100. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 260, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

272.

101. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 261, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

273.

102. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 262, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

274.

103. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 263, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

275.

104. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 264, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

276.

105. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 265, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

277.

106. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 284, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

304.

107. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 285, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

305.

108. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 286, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

306.

109. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 287, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

307.

110. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 288, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

308.

111. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 289, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

309.

112. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 290, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

310.

113. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 291, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

311.

114. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 292, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

312.

115. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 293, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

313.

116. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 324, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

346.

117. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 325, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

347.

118. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 326, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

348.

119. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 327, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

349.

120. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 328, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

350.

121. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 329, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

351.

122. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 330, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

352.

123. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 331, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

353.

124. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 332, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

354.

125. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 333, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

354.

126. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 334, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

356.

127. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 368, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

394.

128. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 369, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

395.

129. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 370, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

396.

130. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 371, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

397.

131. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 372, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

398.

132. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 373, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

399.

133. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 374, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

400.

134. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 375, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

401.

135. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 376, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

402.

136. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 377, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

403.

137. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 378, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

404.

138. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 379, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

405.

139. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 380, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

406.

140. The antibody of any one of claims 16 to 139, wherein the antibody binds CFHR4 and reduces complement activation.

141. The antibody of any one of claims 16 to 140, wherein the antibody has a K of about 100 nM or less. D Binds human CFHR4b.

142. The antibody of any one of claims 16 to 141, wherein the antibody attenuates complement component 3 (C3) convertase activity.

143. The antibody of claim 142, wherein: (a) the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 330, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 352; (b) the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 293, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 313; (c) the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 378, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 404; (d) the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 377, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 403; (e) the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 376, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 402; (f) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 289, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 309; (g) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 371, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 397; or (h) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 284, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:

304.

144. The antibody of any one of claims 16 to 141, wherein the antibody cross-reacts with cynomolgus monkey CFHR4b protein (cCFHR4b).

145. The antibody of claim 144, wherein the antibody comprises a VH region and a VL region that are at least 90% identical to the VH region and VL region of an antibody selected from the group consisting of ATX-P-560, ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-569, ATX-P-570, ATX-P-571, ATX-P-572, ATX-P-573, ATX-P-574, ATX-P-575, ATX-P-576, ATX-P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX-P-583, ATX-P-584, ATX-P-585, ATX-P-586, ATX-P-587, ATX-P-588, ATX-P-589, ATX-P-590, ATX-P-591, ATX-P-592, ATX-P-593, ATX-P-594, ATX-P-595 X-P-573, ATX-P-574, ATX-P-576, ATX-P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, A TX-P-583, ATX-P-587, ATX-P-588, ATX-P-591, ATX-P-592, ATX-P-594, ATX-P-596, ATX-P-600 and ATX-P-604.

146. The antibody of any one of claims 16 to 141, wherein the antibody does not cross-react with cynomolgus monkey CFHR4b protein (cCFHR4b).

147. The antibody of claim 146, wherein the antibody comprises a VH region and a VL region that are at least 90% identical to the VH region and VL region of an antibody selected from the group consisting of: ATX-P-572, ATX-P-595, ATX-P-597, ATX-P-598, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-607, ATX-P-608, ATX-P-609, and ATX-P-610.

148. The antibody of any one of claims 16 to 141, wherein the antibody cross-reacts with complement factor H-related protein 4a (CFHR4a).

149. The antibody of claim 148, wherein the antibody comprises a VH region and a VL region that are at least 90% identical to the VH region and VL region of an antibody selected from the group consisting of ATX-P-560, ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-569, ATX-P-570, ATX-P-571, ATX-P-572, ATX-P-573, ATX-P-574, ATX-P-576, ATX-P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX-P-583, ATX-P-584, ATX-P-585, ATX-P-586, ATX-P-587, ATX-P-588 X-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX-P-583, ATX-P-587, ATX-P-588, ATX-P-591, ATX-P-592, ATX-P-594, ATX-P- 595, ATX-P-596, ATX-P-597, ATX-P-600, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-604, ATX-P-607, ATX-P-608, ATX-P-609 and ATX-P-610.

150. The antibody of any one of claims 16 to 141, wherein the antibody does not cross-react with complement factor H related protein 4a (CFHR4a).

151. The antibody of claim 150, wherein the antibody comprises a VH region and a VL region that are at least 90% identical to ATX-P-598.

152. The antibody of any one of claims 16 to 141, wherein the antibody cross-reacts with complement factor H-related protein 3 (CFHR3).

153. The antibody of claim 152, wherein the antibody comprises a VH region and a VL region that are at least 90% identical to the VH region and VL region of an antibody selected from the group consisting of: ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-569, ATX-P-572, ATX-P-573, ATX-P-574, ATX-P-575, ATX-P-576, ATX-P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX-P-583, ATX-P-584, ATX-P-585, ATX-P-586, ATX-P-587, ATX-P-588, ATX-P-589, ATX-P-590, ATX-P-591, ATX-P-592, ATX-P-593, ATX-P-594, ATX-P-595, ATX-P-596, ATX-P-597, ATX-P-598, ATX-P-599, ATX-P-5 76. ATX-P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-583, ATX-P-587, ATX-P-588, ATX-P-59 2. ATX-P-594, ATX-P-595, ATX-P-596, ATX-P-600, ATX-P-603, ATX-P-604, ATX-P-608, ATX-P-609 and ATX-P-610.

154. The antibody of any one of claims 16 to 141, wherein the antibody does not cross-react with complement factor H related protein 3 (CFHR3).

155. The antibody of claim 154, wherein the antibody comprises a VH region and a VL region that are at least 90% identical to the VH region and VL region of an antibody selected from the group consisting of ATX-P-560, ATX-P-570, ATX-P-571, ATX-P-582, ATX-P-591, ATX-P-597, ATX-P-598, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-604, and ATX-P-607.

156. The antibody of any one of claims 16 to 141, wherein the antibody cross-reacts with complement factor H-related protein 1 (CFHL1).

157. The antibody of claim 156, wherein the antibody comprises a VH region and a VL region that are at least 90% identical to the VH region and VL region of an antibody selected from the group consisting of ATX-P-561, ATX-P-562, ATX-P-563, ATX-P-564, ATX-P-565, ATX-P-566, ATX-P-568, ATX-P-570, ATX-P-571, ATX-P-573, ATX-P-574, ATX-P-575, ATX-P-576, ATX-P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX-P-583, ATX-P-584, ATX-P-585, ATX-P-586, ATX-P-587, ATX-P-588, ATX-P-589, ATX-P-590, ATX-P-591, ATX-P-593, ATX-P-594, ATX-P-595, ATX-P-596, ATX-P-597, ATX-P-598 X-P-574, ATX-P-576, ATX-P-577, ATX-P-578, ATX-P-579, ATX-P-580, ATX-P-581, ATX-P-582, ATX-P- 583, ATX-P-587, ATX-P-588, ATX-P-591, ATX-P-594, ATX-P-595, ATX-P-596, ATX-P-600 and ATX-P-604.

158. The antibody of any one of claims 16 to 141, wherein the antibody does not cross-react with complement factor H-related protein 1 (CFHL1).

159. The antibody of claim 158, wherein the antibody comprises a VH region and a VL region that are at least 90% identical to the VH region and VL region of an antibody selected from the group consisting of: ATX-P-560, ATX-P-569, ATX-P-572, ATX-P-592, ATX-P-597, ATX-P-598, ATX-P-601, ATX-P-602, ATX-P-603, ATX-P-607, ATX-P-608, ATX-P-609, and ATX-P-610.

160. The antibody of any one of claims 16 to 159, wherein the antibody is a monoclonal antibody, a human antibody, a humanized antibody and / or a chimeric antibody.

161. The antibody of any one of claims 16 to 160, wherein the antibody is a fragment selected from the group consisting of: Fab, Fab-C, Fab'-SH, Fv, scFv and (Fab')2 fragment.

162. The antibody of any one of claims 16 to 161, wherein the antibody is a monospecific antibody.

163. The antibody of any one of claims 16 to 162, wherein the antibody is a bispecific antibody.

164. The antibody of any one of claims 16 to 163, wherein the antibody comprises a detection moiety.

165. The antibody of any one of claims 16 to 164, wherein the antibody comprises a purification portion.

166. The antibody of any one of claims 16 to 165, wherein the antibody comprises a half-life extending moiety.

167. The antibody of claim 166, wherein the half-life extending portion comprises a polypeptide of at least 20 amino acids in length and comprising any combination of G, A, ST, E, and P residues.

168. The antibody of claim 167, wherein the half-life extending polypeptide is linked to the C-terminus or N-terminus of the antibody.

169. A pharmaceutical composition comprising the antibody of any one of claims 1 to 168.

170. The composition of claim 169, wherein the composition is suitable for ocular administration.

171. The composition of claim 170, wherein the ocular administration comprises injection into the vitreous humor.

172. The composition of claim 170, wherein the ocular administration comprises delivering the antibody using a conjunctival insert, a contact lens, a gel, nanoparticles, a mucoadhesive polymer, an ointment, a solution, a suspension, eye drops, and / or an implant.

173. A method of treating age-related macular degeneration (AMD), the method comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of the antibody of claim 1 or claim 2.

174. The method of claim 173, wherein the pharmaceutical composition is administered ocularly and treats at least one symptom of AMD.

175. The method of claim 174, wherein AMD comprises wet AMD.

176. The method of claim 174, wherein AMD comprises dry AMD.

177. The method of any one of claims 173-176, wherein the at least one AMD symptom comprises visual distortion, decreased central vision, blurred vision, and / or difficulty adapting to dim light.

178. The method of any one of claims 173-177, wherein administration of the pharmaceutical composition reduces complement activation in the eye of the subject.

179. The method of any one of claims 173-178, wherein the pharmaceutical composition is administered at a dose ranging from about 0.0001 mg / dose to about 100 mg / dose.

180. The method of any one of claims 173-178, wherein the pharmaceutical composition is administered at a dose ranging from about 0.0001 mg / ml to about 100 mg / ml.

181. A polynucleotide having at least 70% identity to any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NOs: 335-345; or (d) SEQ ID NO: 381-393.

182. A polynucleotide having at least 70% identity to any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NOs: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NOs: 407-419.

183. A polynucleotide having at least 80% identity to any of the following nucleic acid sequences: (a) SEQ ID NO: 266-271; (b) SEQ ID NO: 294-303; (c) SEQ ID NOs: 335-345; or (d) SEQ ID NOs: 380-393.

184. A polynucleotide having at least 80% identity to any of the following nucleic acid sequences: (a) SEQ ID NO: 278-283; (b) SEQ ID NOs: 314-323; (c) SEQ ID NO: 357-367; or (d) SEQ ID NOs: 407-419.

185. A polynucleotide comprising: (a) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 266 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 278; (b) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 267 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 279; (c) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 268 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 280; (d) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 269 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 281; (e) a nucleic acid sequence at least 90% identical to SEQ ID NO: 270 and a nucleic acid at least 90% identical to SEQ ID NO: 282; or (f) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 270 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO:

283.

186. A polynucleotide comprising: (a) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 294 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 314; (b) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 295 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 315; (c) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 296 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 316; (d) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 297 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 317; (e) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 298 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 318; (f) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 299 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 319; (g) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 300 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 320; (h) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 301 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 321; (i) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 302 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 322; or (j) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 303 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO:

323.

187. A polynucleotide comprising: (a) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 335 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 357; (b) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 336 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 358; (c) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 337 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 359; (d) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 338 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 360; (e) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 339 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 361; (f) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 340 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 362; (g) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 341 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 363; (h) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 342 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 364; (i) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 343 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 365; (j) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 344 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 366; or (k) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 345 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO:

367.

188. A polynucleotide comprising: (a) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 381 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 407; (b) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 382 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 408; (c) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 383 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 409; (d) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 384 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 410; (e) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 385 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 411; (f) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 386 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 412; (g) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 387 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 413; (h) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 388 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 414; (i) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 389 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 415; (j) a nucleic acid sequence at least 90% identical to SEQ ID NO: 390 and a nucleic acid at least 90% identical to SEQ ID NO: 416; (k) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 391 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 417; (1) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 392 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 418; or (m) a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 393 and a nucleic acid sequence that is at least 90% identical to SEQ ID NO:

419.

189. An expression vector comprising the polynucleotide of any one of claims 181-188.

190. The expression vector of claim 189, wherein the expression vector is at least one of an adeno-associated virus (AAV) vector, a lentivirus (LV) vector, a herpes simplex virus (HSV) vector, and a retrovirus vector.

191. A method of administering ocular gene therapy to a subject in need thereof, the method comprising injecting a pharmaceutical composition comprising an effective amount of the expression vector of claim 190.

192. A method for treating age-related macular degeneration (AMD), the method comprising administering a pharmaceutical composition comprising an effective amount of an expression vector as described in claim 190, wherein administering the pharmaceutical composition treats at least one symptom of AMD.

193. The antibody of any one of claims 16 to 168, wherein the antibody binds to an epitope of a CFHR4b polypeptide having the amino acid sequence of SEQ ID NO: 580.

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