Astrotactin1-based compositions and pharmaceutical formulations

Abstract

Methods of detecting, preventing, treating, controlling or managing progressive neurodegenerative diseases are provided. These methods comprise the administration of antibodies that reduce or eliminate monocytes that abnormally express Astrotactin (ASTNI), or block blood monocytes that abnormally express ASTNI from migrating to the central nervous system. Also provided are pharmaceutical compositions that comprise antibodies that specifically target the extracellular domain (ECD2) of ASTNI for the prevention, treatment, control or management of progressive neurodegenerative diseases.

1 . A method of administering an antibody or fragment thereof, comprising the steps of:
 detecting expression of astrotactin (ASTNI) in a subject's blood monocytes; and   administering to the subject an amount of the antibody or fragment thereof, comprising a heavy chain variable region (VR) and a light chain VR.   
     
     
         2 . The method of  claim 1 , wherein the heavy chain VR comprises an amino acid sequence of SEQ ID NO: 1, and wherein the light chain VR comprises an amino acid sequence of SEQ ID NO:2. 
     
     
         3 . The method of  claim 1 , wherein the heavy chain variable region (VR) and alight chain VR, wherein the heavy chain VR comprises an amino acid sequence of SEQ ID NO: 3, and wherein the light chain VR comprises an amino acid sequence of SEQ ID NO: 4. 
     
     
         4 . The method of  claim 1 , wherein the antibody or fragment thereof binds one or more residues in ASTNI extracellular domain, and wherein the heavy chain VR comprises heavy chain CDRs comprising anyone of SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7, and wherein the light chain VR comprises light chain CDRs comprising anyone of SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. 
     
     
         5 . The method of  claim 4 , wherein the one or more residues in ASTNI extracellular domain comprise one or more of Phe757, Arg758, Gln759, Asn760, Asn761, Phe762, Ala763, Arg764, Gly765, Leu766, Asp767, Gln768, Gln769, Va1775, Va1776, Ala777, Thr778, Va1808, Arg888, Arg911, Lys931, His932, Ala935, Thr1073, Asp1074, Arg1075, Met1076, Asp1077, His1078, Ser1079, Lys1080, Va11081, Glu1082, Thr1083, Thr1085, Leu1087, Asp1092, Ser1095, Gly1096, Ala1097, Lys1098, Serl 099, Prol 100, Cyst 101, Alal 102, Ilel 119, Glul 123, Prol 124, Lysl 160, Glul 163, Ilel 164, Lysl 167, Asnl 168, Thrl 176, Glnl 182, Thrl 183, Tyrl 185, Asnl 186, Leul 189, Aspl 190, Leul 191, Glyl 192, Serl 193, Tyr1201, Gln1205, His1206, Glu1208, Ser1209, Glu1212, Trp1215, Glu1218, Pro1223, Arg1224, Gly1227, Leu1230, Ser1231, Gln1232, Gly1234, Asp1235, Gln1245, Glu1246, Pro1247, Tyr1296, Gly1297, Asp1298, Ser1299, or Lys1300. 
     
     
         6 . The method of  claim 1 , wherein the heavy chain VR comprises heavy chain CDRs comprising any one of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13, and wherein the light chain VR comprises light chain CDRs comprising anyone of SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16. 
     
     
         7 . The method of  claim 6 , wherein the one or more residues in ASTNI extracellular domain comprise one or more of Phe757, Arg758, Gln759, Asn760, Asn761, Phe762, Ala763, Arg764, Gly765, Leu766, Asp767, Gln768, Gln769, Va1775, Va1776, Ala777, Thr778, Va1808, Arg888, Arg911, Lys931, His932, Ala935, Thr1073, Asp1074, Arg1075, Met1076, Asp1077, His1078, Ser1079, Lys1080, Va11081, Glu1082, Thr1083, Thr1085, Leu1087, Asp1092, Ser1095, Gly1096, Ala1097, Lys1098, Sen 099, Prol 100, Cysl 101, Alal 102, Ilel 119, Glul 123, Prol 124, Lysl 160, Glul 163, Ilel 164, Lysl 167, Asnl 168, Thrl 176, Ginl 182, Thrl 183, Tyrl 185, Asnl 186, Leul 189, Aspl 190, Leul 191, Glyl 192, Serl 193, Tyr1201, Gln1205, His1206, Glu1208, Ser1209, Glu1212, Trp1215, Glu1218, Pro1223, Arg1224, Gly1227, Leu1230, Ser123 1, Gln1232, Gly1234, Asp1235, Gln1245, Glu1246, Pro1247, Tyr1296, Gly1297, Asp1298, Ser1299, or Lys1300. 
     
     
         8 . The method of  claim 1 , wherein the antibody or fragment thereof binds one or more residues in the astrotactin (ASTNI) extracellular domain 1205-1208 region, and wherein the one or more residues comprise one or more of Gln1205, His1206, Tyr1207 and Glu1208. 
     
     
         9 . The method of  claim 1 , wherein the antibody or fragment thereof are conjugated with a cytotoxic drug to form antibody-drug conjugates (ADCs), such that the antibodies or fragments thereof may detect ASTNI and attach to the surface of blood monocytes carrying ASTNI. 
     
     
         10 . The method of  claim 1 , further comprising the steps of:
 administering the antibody or fragment thereof in the form of a stable liquid aqueous pharmaceutical formulation comprising the antibody or fragment thereof, a tonicity agent, a surfactant, and a buffer, and wherein the liquid aqueous pharmaceutical formulation optionally further comprises one or more pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavor-imparting agents or pharmaceutically acceptable carriers suitable for enteral, parenteral, or intravenous administration.   
     
     
         11 . The method of  claim 1 , further comprising the steps of:
 administering to the subject one or more of a chemotherapeutic agent, an immunosuppressive agent, an immuno-stimulatory agent, an anti-pyretic agent, a cytotoxic agent, a nucleolytic compound, a radioactive isotope, a receptor, a pro-drug activating enzyme, an anti-inflammatory agent, an antibiotic, a protease inhibitor, a growth factor, an osteo-inductive factor, an antibacterial agent or an antifungal agent.   
     
     
         12 . The method of  claim 1 , further comprising the steps of:
 detecting expression of one or more cytokines, or one or more signaling pathway in the subject.   
     
     
         13 . The method of  claim 12 , wherein the cytokine is one or more of IL-lb, IL-6 or TNF. 
     
     
         14 . The method of  claim 12 , wherein the signaling pathway is one or more of Janus tyrosine Kinase (JAK) pathway, or Signal Transducer and Activator of Transcription (STAT) pathway.