HBM variants that modulate bone mass and lipid levels

Abstract

The present invention relates to methods and materials used to express an HBM-like polypeptide derived from HBM, LRP5 or LRP6 in animal cells and transgenic animals. The present invention also relates to transgenic animals expressing the HBM-like polypeptides. The invention provides nucleic acids, including coding sequences, oligonucleotide primers and probes, proteins, cloning vectors, expression vectors, transformed hosts, methods of developing pharmaceutical compositions, methods of identifying molecules involved in bone development, and methods of diagnosing and treating diseases involved in bone development and lipid modulation. In preferred embodiments, the present invention is directed to methods for treating, diagnosing and preventing osteoporosis.

1 - 20 . (canceled) 
     
     
         21 . An antibody or immunogenic fragment thereof which binds to a polypeptide or biologically active fragment thereof derived from LRP5 comprising at least one amino acid change of Table 2, G171V, A214V, A65V, M282V, G171K, G171F, G171I, G1710Q, L200V, T201V, 1202V, or S127V, or binds to a polypeptide or biologically active fragment thereof derived from LRP6 comprising at least one amino acid change of Table 2, G171V, A214V, A65V, M282V, G171K, G171F, G1711, G1710Q, L200V, T201V, I1202V, or S127V when the amino acid change is expressed in an equivalent position in LRP6. 
     
     
         22 . The antibody or immunogenic fragment thereof of  claim 21 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a bispecific antibody, a humanized antibody, a primatized antibody, a human antibody, or a labeled antibody. 
     
     
         23 . An antibody which binds to a polypeptide comprising  208 KLYWADAKLSFIHRAN 223 ,  277 ALYSPMDIQVLSQER 291 ,  61 GLEDAAAVDFQFSKGA 73 ,  234 EGSLTHPFALTLSG 247 ,  249 TLYWTDWQTRSIHACN 264 ,  144 VLFWQDLDQPRAI 156 ,  194 IYWPNGLTIDLEEQKLY 210 ,  34 LLLFANRRDVRLVD 47 ,  75 GAVYWTDVSEEAIKQ 89 ,  121 KLYWTDSETNRIEVA 135  of LRP5 or an equivalent domain on LRP6 or variants thereof. 
     
     
         24 . An antibody which binds to a polypeptide comprising  969 LILPLHGLRNVKAIDYDPLDKFIYW 993 ,  989 KFIYWVDGRQNIKRAKDDGTQPFVL 1013 ,  1009 QPFVLTSLSQGQNPDRQPHDLSIDI 1033 ,  1029 LSIDIYSRTLFWTCEATNTINVHRL 1053 ,  1049 NVHRLSGEAMGVVLRGDRDKPRAIV 1073 ,  1253 CGEPPTCSPDQFAC 1266 ,  1278 WRCDGFPECDDQSDEEGC 1295 ,  1316 RCDGEADCQDRSDEADC 1332 ,  1370 CEITKPPSDDSPAH 1383  of LRP5 or an equivalent domain on LRP6 or variants thereof, wherein said antibody modulates binding of LRP5, HBM, LRP6 or variants thereof to Dkk. 
     
     
         25 . (canceled) 
     
     
         26 . A composition for modulating bone mass and/or lipid levels in a subject comprising a therapeutically effective amount of an antibody of  claim 21  and a pharmaceutically acceptable carrier. 
     
     
         27 . An antibody or an immunogenic fragment thereof of  claim 21 , wherein the antibody or immunogenic fragment thereof can (1) discriminate between LRP5 and an HBM-like protein, (2) discriminate between LRP6 and an HBM-like protein, or (3) discriminate between HBM and an HBM-like protein. 
     
     
         28 - 48 . (canceled)