Compositions and methods of use for therapeutic low density lipoprotein - related protein 6 (lrp6) multivalent antibodies

Abstract

The present invention relates to antibodies targeting LRP6 and compositions and methods of use thereof.

1 .- 108 . (canceled) 
     
     
         109 . A multivalent antibody, or an antibody fragment thereof, comprising at least two receptor binding domains for two different binding sites of an LRP6 target receptor, wherein the first receptor binding domain binds to the β-propeller 1 domain, and the second receptor binding domain binds to the β-propeller 3 domain on the same LRP6 target receptor, and wherein the multivalent antibody inhibits β-propeller 1-mediated Wnt 1 signalling and β-propeller 3-mediated Wnt3a signalling and displays no significant potentiation of a Wnt signal. 
     
     
         110 . The multivalent antibody or antibody fragment of  claim 109 , wherein the first and/or second receptor binding domain comprises an IgG antibody, an scFv fragment, or an antibody variable region. 
     
     
         111 . The multivalent antibody or antibody fragment of  claim 109 , wherein the first receptor binding domain is a first antibody variable region and the second receptor binding domain is a second antibody variable region. 
     
     
         112 . The multivalent antibody or antibody fragment of  claim 109 , wherein the first and second receptor binding domains each comprises a camelid antibody or a camelid nanobody. 
     
     
         113 . The multivalent antibody or antibody fragment of  claim 109 , wherein the first and second receptor binding domains each comprises a single domain antibody. 
     
     
         114 . The multivalent antibody or antibody fragment of  claim 109 , wherein the first and second receptor binding domains each comprises a single variable domain or a VHH. 
     
     
         115 . The multivalent antibody or antibody fragment of  claim 109 , wherein the first receptor binding domain and the second receptor binding domain are separated by a linker. 
     
     
         116 . The multivalent antibody or antibody fragment of  claim 115 , wherein the linker comprises Gly and Ser. 
     
     
         117 . The multivalent antibody or antibody fragment of  claim 115 , wherein the linker comprises (Gly 4 Ser) 4  or (Gly 4 Ser) 3 . 
     
     
         118 . The multivalent antibody or antibody fragment of  claim 109 , wherein the multivalent antibody is a bivalent antibody, a bispecific antibody, or a biparatopic antibody. 
     
     
         119 . The multivalent antibody or antibody fragment of  claim 109 , further comprising an Fc domain. 
     
     
         120 . The multivalent antibody or antibody fragment of  claim 109 , further comprising a half-life extending moiety. 
     
     
         121 . The multivalent antibody or antibody fragment of  claim 120 , wherein the half-life extending moiety is an Fc domain or a moiety that binds to a serum protein. 
     
     
         122 . The multivalent antibody or antibody fragment of  claim 121 , wherein the serum protein is an albumin, an IgG, an FcRn, or a transferrin. 
     
     
         123 . The multivalent antibody or antibody fragment of  claim 121 , wherein the serum protein is albumin. 
     
     
         124 . The multivalent antibody or antibody fragment of  claim 123 , wherein the moiety that binds to albumin is a nanobody, a Fab, a DARPin, an avimer, an affibody, or an anticalin. 
     
     
         125 . The multivalent antibody or antibody fragment of  claim 123 , wherein the moiety that binds to albumin comprises a camelid nanobody, a single domain antibody, or a VHH. 
     
     
         126 . The multivalent antibody or antibody fragment of  claim 120 , wherein the half-life extending moiety comprises an albumin, a domain of albumin, or an albumin-binding protein. 
     
     
         127 . A biparatopic antibody, or biparatopic antibody fragment thereof, comprising at least two VHHs that bind two different binding sites of an LRP6 target receptor, wherein the first VHH binds to the β-propeller 1 domain of LRP6, and the second VHH binds to the β-propeller 3 domain of LRP6, wherein the biparatopic antibody inhibits β-propeller 1-mediated Wnt1 signalling and β-propeller 3-mediated Wnt3a signalling and displays no significant potentiation of a Wnt signal, and wherein the biparatopic antibody further comprises a moiety that binds to albumin. 
     
     
         128 . The biparatopic antibody or biparatopic antibody fragment of  claim 127 , wherein the moiety that binds to albumin comprises a camelid nanobody, a single domain antibody, or a VHH. 
     
     
         129 . A bispecific antibody, or antibody fragment thereof, comprising at least two VHHs that bind two different binding sites of an LRP6 target receptor, wherein the first VHH binds to the β-propeller 1 domain of LRP6, and the second VHH binds to the β-propeller 3 domain of LRP6, wherein the biparatopic antibody inhibits β-propeller 1-mediated Wnt 1 signalling and β-propeller 3-mediated Wnt3a signalling and displays no significant potentiation of a Wnt signal, and wherein the biparatopic antibody further comprises an Fc domain.