Methods of increasing progranulin levels using anti-sortilin antibodies

Abstract

The present disclosure is generally directed to compositions that include antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind on or more epitopes within a Sortilin protein, e.g., human Sortilin or a mammalian Sortilin, and use of such compostions in preventing, reducing risk, or treating an individual in need thereof.

1 - 93 . (canceled) 
     
     
         94 . A method of increasing Progranulin levels in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated anti-Sortilin antibody,
 wherein the anti-Sortilin antibody increases extracellular levels of Progranulin and decreases cellular levels of Sortilin, wherein the decrease in cellular levels of Sortilin is a decrease in cell surface levels of Sortilin, a decrease in intracellular levels of Sortilin, a decrease in total levels of Sortilin, or any combination thereof; and   wherein the anti-Sortilin antibody does not inhibit the interaction between Sortilin and Progranulin.   
     
     
         95 . The method of  claim 94 , wherein levels of Progranulin are increased in the brain, blood, and/or one or more peripheral organs of the individual. 
     
     
         96 . The method of  claim 94 , wherein the anti-Sortilin antibody induces Sortilin degradation, Sortilin cleavage, Sortilin internalization, Sortilin down regulation, or any combination thereof. 
     
     
         97 . The method of  claim 94 , wherein the anti-Sortilin antibody inhibits interaction between Sortilin and one or more proteins by: a) reducing the effective levels of Sortilin available for interacting with the one or more proteins; b) inducing degradation of Sortilin; or both. 
     
     
         98 . The method of  claim 94 , wherein the anti-Sortilin antibody inhibits interaction between Sortilin and pro-nerve growth factor (pro-NGF). 
     
     
         99 . The method of  claim 94 , wherein the anti-Sortilin antibody does not inhibit interaction between Sortilin and pro-nerve growth factor (pro-NGF). 
     
     
         100 . The method of  claim 94 , wherein the anti-Sortilin antibody binds specifically to human Sortilin and mouse Sortilin. 
     
     
         101 . The method of  claim 100 , wherein the anti-Sortilin antibody:
 (a) binds with a dissociation constant (K D ) for human Sortilin that ranges from about 0.005 nM to about 100 nM; and/or   (b) binds with a dissociation constant (K D ) for mouse Sortilin that ranges from about 0.005 nM to about 100 nM.   
     
     
         102 . The method of  claim 94 , wherein the anti-Sortilin antibody:
 (a) induces one or more Progranulin activities;   (b) reduces endosomal internalization of Progranulin, or fragments thereof; and/or   (c) increases the effective concentration of Progranulin.   
     
     
         103 . The method of  claim 94 , wherein the anti-Sortilin antibody does not inhibit the interaction between Sortilin and Progranulin in vitro. 
     
     
         104 . The method of  claim 103 , wherein the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein:
 the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 126, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 150, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 486, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 503, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 194;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 147, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 173, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 253;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 28, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 62, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 197;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 69, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 135, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 162, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 203;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 156, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 195;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 34, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 58, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 157, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 193;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 68, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 135, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 162, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 203;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 61, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 157, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 196;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 91, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 140, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 166, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 225;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 89, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 140, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 166, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 223;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 185;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 319, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 320;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 319, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 614;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 350, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 351;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 472, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 473;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 356, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 357;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 370, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 369;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 352, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 353;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 348, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 349;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 368, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 369;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 354, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 355;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 413, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 414;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 409, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 410; or   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 330, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 331.   
     
     
         105 . The method of  claim 103 , wherein:
 (a) the anti-Sortilin antibody competes with a reference anti-Sortilin antibody for binding to human Sortilin, and/or   (b) the anti-Sortilin antibody binds to an epitope of human Sortilin that is the same as the Sortilin epitope bound by a reference anti-Sortilin antibody;   wherein the reference anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein:
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 126, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 150, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 486, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 503, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 194; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 147, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 173, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 253; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 28, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 62, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 197; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 69, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 135, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 162, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 203; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 156, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 195; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 34, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 58, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 157, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 193; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 68, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 135, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 162, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 203; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 61, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 157, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 196; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 91, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 140, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 166, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 225; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 89, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 140, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 166, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 223; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 185; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 319, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 320; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 319, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 614; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 350, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 351; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 472, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 473; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 356, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 357; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 370, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 369; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 352, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 353; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 348, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 349; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 368, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 369; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 354, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 355; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 413, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 414; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 409, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 410; or 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 330, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 331. 
   
     
     
         106 . The method of  claim 94 , wherein the anti-Sortilin antibody does not inhibit the interaction between Sortilin expressed on a cell and Progranulin. 
     
     
         107 . The method of  claim 106 , wherein the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein:
 the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 126, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 150, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 486, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 503, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 194;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 147, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 173, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 253;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 28, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 62, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 197;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 69, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 135, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 162, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 203;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 156, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 195;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 34, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 58, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 157, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 193;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 68, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 135, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 162, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 203;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 61, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 157, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 196;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 91, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 140, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 166, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 225;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 129, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 155, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 190;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 95, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 169, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 229;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 101, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 169, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 234;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 89, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 140, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 166, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 223;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 103, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 169, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 236;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 112, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 175, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 244;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 15, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 104, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 169, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 236;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 106, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 144, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 172, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 238;   the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 116, and the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 144, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 173, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 247;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 319, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 320;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 319, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 614;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 350, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 351;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 472, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 473;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 356, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 357;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 370, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 369;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 352, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 353;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 348, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 349;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 368, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 369;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 354, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 355;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 413, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 414;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 341, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 342;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 421, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 422;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 432, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 433;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 409, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 410;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 436, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 437;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 453, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 454;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 438, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 437;   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 441, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 442; or   the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 460, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 461.   
     
     
         108 . The method of  claim 106 , wherein:
 (a) the anti-Sortilin antibody competes with a reference anti-Sortilin antibody for binding to human Sortilin, and/or   (b) the anti-Sortilin antibody binds to an epitope of human Sortilin that is the same as the Sortilin epitope bound by a reference anti-Sortilin antibody;   wherein the reference anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein:
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 126, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 150, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 486, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 503, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 180; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 194; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 122, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 147, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 173, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 253; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 28, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 62, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 197; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 69, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 135, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 162, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 203; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 156, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 195; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 34, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 58, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 157, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 193; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 68, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 135, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 162, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 203; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 61, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 157, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 196; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 91, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 140, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 166, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 225; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 129, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 155, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 190; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 95, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 169, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 229; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 101, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 169, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 234; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 89, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 140, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 166, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 223; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 103, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 169, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 236; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 32, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 112, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 175, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 244; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 15, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 104, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 169, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 236; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 106, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 144, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 172, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 238; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 116, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 144, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 173, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 247; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 319, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 320; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 319, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 614; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 350, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 351; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 472, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 473; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 356, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 357; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 370, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 369; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 352, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 353; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 348, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 349; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 368, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 369; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 354, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 355; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 413, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 414; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 341, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 342; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 421, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 422; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 432, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 433; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 409, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 410; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 436, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 437; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 453, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 454; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 438, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 437; 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 441, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 442; or 
 the light chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 460, and the heavy chain variable domain of the reference anti-Sortilin antibody comprises the amino acid sequence of SEQ ID NO: 461. 
   
     
     
         109 . The method of  claim 94 , wherein the anti-Sortilin antibody is a human antibody, a humanized antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody. 
     
     
         110 . The method of  claim 94 , wherein the anti-Sortilin antibody is a multivalent antibody recognizing a second antigen. 
     
     
         111 . The method of  claim 110 , wherein the second antigen is an antigen facilitating transport across the blood-brain-barrier. 
     
     
         112 . The method of  claim 111 , wherein the second antigen is selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, TMEM 30(A), a protein transduction domain, TAT, Syn-B, penetratin, a poly-arginine peptide, an angiopep peptide, and ANG1005. 
     
     
         113 . The method of  claim 94 , wherein the anti-Sortilin antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human Sortilin or a mammalian Sortilin protein, and wherein the antibody fragment is an Fab, Fab′, Fab′-SH, F(ab′) 2 , Fv, or scFv fragment. 
     
     
         114 . The method of  claim 94 , wherein the anti-Sortilin antibody has an IgG1 or IgG4 isotype. 
     
     
         115 . The method of  claim 114 , wherein:
 (a) the anti-Sortilin antibody has a human IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU numbering; or   (b) the anti-Sortilin antibody has a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: E233P, F234V, L234A/F234A, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein the numbering of the residues is according to EU numbering.   
     
     
         116 . The method of  claim 115 , wherein:
 (a) the IgG1 Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of A330L, L234F, L235E, P331S, and any combination thereof, wherein the numbering of the residues is according to EU numbering;   (b) the IgG1 or IgG4 Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU numbering; or   (c) the IgG4 Fc region further comprises a S228P amino acid substitution according to EU numbering.   
     
     
         117 . The method of  claim 114 , wherein: (a) the anti-Sortilin antibody has a human IgG4 isotype and comprises an amino acid substitution at residue positions S228P, F234A, and L235A, wherein the numbering of the residue position is according to EU numbering; or (b) the anti-Sortilin antibody has a human IgG1 isotype and comprises an amino acid substitution at residue positions L234A, L235A, and P331S, wherein the numbering of the residue position is according to EU numbering.