Crimped receptor antibodies and uses thereof

Abstract

The invention relates to crimping receptor antibodies and uses thereof. Isolated antibodies and immunoconjugates that specifically bind to a cysteine rich domain (CRD) of a frizzled receptor (FZD) 4 comprising a light chain variable region and a heavy chain variable region, the heavy chain variable region comprising complementary determining regions CDR-H1, CDR-H2, and CDR-H3, the light chain variable region comprising complementary determining regions CDR-L1, CDR-L2, and CDR-L3, and the amino acid sequence of the CDR comprises a sequence selected from a sequence in table 1a or table 3a or consists of a sequence selected from a sequence in table 1a or table 3a. Methods of using the antibodies and immunoconjugates are also provided.

Claims

1. An antibody that specifically binds to a cysteine-rich domain (CRD) of each of one or more than one human frizzled receptors selected from FZD1, FZD2, FZD4, FZD5, FZD7, FZD8, and FZD9, the antibody comprising a light chain variable region and / or a heavy chain variable region, the heavy chain variable region comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, the light chain variable region comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3, wherein the amino acid sequence of the CDR comprises or consists of a sequence selected from the sequence in Table 1a or Table 3a.

2. The antibody according to claim 1, wherein the amino acid sequence of the CDR comprises or consists of a sequence selected from the group consisting of: CDR-H1 is selected from the group consisting of: LYYTDM, IYFSSI, IGSSSI, VNSSSI, IHFSSI, IYSASI, IHSSSI, IYFSSI, IYSSSI, LSYSFF , LSFYFL, LSSYYM, SSFYFM, LSYYYM, IASYFT, FSSSSI, LSYYFM, IYYYPM, FSAYNI, IYYFGM, IHSSSI and ISYHYM; CDR-H2 is selected from the group consisting of: SISLFFGYVS, SNYPSFGSNS, SIYSAFASTS, AFYSSFGATS, AYYSAFASSS, CSYPSFGSTS, SRYPSFGSTS, AIYSSFSANS, SNYPAFGSTS, SIYSAFLSTT, SIYPSSGYTY, SIYPYSGYTY, SIYPFHAS TY, TVYPYLDYTY, SIYPYSRNTF, SIYPFSGYST, SIYPYYAYTY, SIYLSFGYGY, CCNSAYRYGP, SIYPYAGNTY, SFYSYYSFTY, SLYTSYGYTY, YIYPFNGYSY, YIYPSYDYTY, YISPPYGFTY, ATYSSFGSIT and SIYPNLGYTY; CDR-H3 is selected from the group consisting of: YHPFGYAL, YLAM, YHFPFAYSL, YHFPFGFAL, YHFPFGHAL, YHYPFGHAL, YHYPFGHAL, YHYPFGTAL, YHYPFGYAL, YHYPFGYAM, YHYPHGHAL, PAPFSYHVL, AAPGSYHPM, AAPYFY GVM, AFPGSYHPM, AYPFSYHFM, PSAFSYHPM, PVAGAYHPM, SSLGFYNGM, TVRGSKKPYFSGWAM, TYPGYYYIL, SGVGGDHAL, VWYVVQ, GYFYTWGGM, GYFYTWGGM, GYYYSWGGM, YHPFGYAL and AYPFSYHYM; CDR-L1 is SVSSA; CDR-L2 is SASSLYS; and / or CDR-L3 is selected from the group consisting of: AAYHWPPLF, GVYLF, SSYSLI, WAYGPF, YYHPI and YYSLF.

3. The antibody according to claim 1, wherein the amino acid sequence of the CDR comprises or consists of a sequence selected from the group consisting of: CDR-H1 is selected from the group consisting of: ISYYYM, IYSYYM, LSYYYM, IYYYSI, LYSYYM, LSSYSM, ISYYYI, LSYSSM, IYYYYM, LYYYSI, IS SYYI, FSSSSI, LSYYSI, LYSYYI, LSSYYM, LSYYYI, ISSYYM, LSYYSM, LYSYSI, LYYYYI, IYSYYI, ISYSYI and ISYYSM; CDR-H2 is selected from the group consisting of: SIYSYYGYTY, SIYSSSSSTY, SIYPSSSYTY, SIYSSSSYTS, YISSYSGSTY, SIYSSYGYTY, YISSYYGYTY, SIYPSSSSTY, SIYSSSGYTY, YISSYSGSTS, SISSYYGSTY, SIYSYYGSTY, SIYPYSGYTY, YISPYYGYTS, SISSSSGYTY, SIYSYSSSTY, SISPSSSYTY, YISPYYGYTY, SISPYSSSTY, SIYSSYGSTY, SIYSSSSYTY, SIYPSSGYTY, SIYPYSGSTY, SIYPSYGSTY, YISSYSSYTY, SIYSYYSSTY, YISSSYGYTS, SISPYSSYTY, YISPYSGYTS, SIYPYYSYTY, SISPYYGYTS, SISPSYSSTY, SISSSYSSTY, SIYPYSGSTS, SISSYYSSTS and SIYSYSGYTY; CDR-H3 is selected from the group consisting of: SSFSWAM, SSFYWAL, SWFGWGI, YWFSYGYASYPAF, HPWYGM, SAFYWAL, PAPGHWGF, SSFFWAM, SAFYWAM, HFFAM, SWWAWAF, SAFGWAL, SSFFFAM, PYYWSGGF, HPSSSWFSFGAL, SAFYWAF, SSYAWAM, SSFYWAI, SPWGSGWAGF, PAVWVGL, SWVFWAL, SWVYWGM, SWVYWAL, SSYAWAI, SSFYWAM, HGASFGSGAPAF, SCFFWAM, WAFFGL, SSFYFAM, SAFSWAI, SGFYWAL, PSVGYAAF, SWVGWGL, SSVGYVAM, SWVYWAF, YYYSSSVYFWYAAL, SSFFWAI, SWVYWAI, SWVGWGI, SSVYWAL, WGGWGSGGYFYAAL, FWYPGM and SSFAWAF; CDR-L1 is SVSSA; CDR-L2 is SASSLYS; and / or CDR-L3 is selected from the group consisting of: HPWSGGYLI, PVGYWGVPI, VSGGAHALI, VSSAYPI, FWGVPI, SYYHYAALI, WYYAPI, SHSYSLI, SGYGPF, SWSSPI, HYSVYASLI, PHPPSLI, VAYSHVGLI, GYGAPI, SWYSLI, PGYLF, VWFGLI, VYYGSPLF, HAHSPLI, SSAYYPF, GHASPI , SSGGWSLI, VAWSSFLI, SVAAASLI, SGWWGVSLI, SYAAYLF, HGSLF, YAGVSNLF, GWPYSALF, SGYYPSLF, SYHSGSGLI, HGYS ASLI, APGWALF, GHSSPI, GWPSLF, VPGYPVPI, HYYSHLI, GPASSLI, SVGSSYYLI, YYGPWVLI, AASWGYPF, HWSYPI and GGWGPF.

4. The antibody according to claim 2 or 3, wherein the antibody comprises a heavy chain variable region comprising: i) the heavy chain amino acid sequence as listed in Table 2; ii) an amino acid sequence that has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to a heavy chain amino acid sequence as listed in Table 2, wherein the CDR sequence is a set of CDR sequences as listed in Table 1a or Table 3a, or iii) the conservatively substituted amino acid sequence of i), wherein the CDR sequence is a CDR sequence set as listed in Table 1a or Table 3a.

5. The antibody according to any one of claims 2 to 4, wherein the antibody comprises a light chain variable region comprising: i) the light chain amino acid sequence as listed in Table 2; ii) an amino acid sequence that has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to a light chain amino acid sequence as listed in Table 2, wherein the CDR sequence is a set of CDR sequences as listed in Table 1a or Table 3a, or iii) the conservatively substituted amino acid sequence of i), wherein the CDR sequence is a CDR sequence set as listed in Table 1a or Table 3a.

6. The antibody of any one of claims 1 to 5, wherein the CDR sequence is selected from the full set of CDR sequences of the antibodies identified in Table 1a or Table 3a.

7. The antibody of any one of claims 1 to 5, wherein the CDR sequence comprises a set of light chain or heavy chain CDR sequences selected from the antibodies identified in Table 1a or Table 3a.

8. The antibody of any one of claims 1 to 7, wherein the antibody specifically binds to FZD4.

9. The antibody of claim 8, wherein the CDR sequence is a set of CDR sequences of an antibody selected from the group consisting of 5017, 5027, 5030, 6499, 5038, 5040-5044, 5046, 5047, 5049-5053, 5055, 5058-5064, 5066, 5068-5072, 5077-5080, or 5081.

10. The antibody of any one of claims 1 to 7, wherein the antibody specifically binds FZD4 and at least one other FZD receptor selected from FZD1, FZD2, FZD5, FZD7, FZD8, and FZD9.

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