Therapeutic targeting of Lewis(y) and Lewis(b) with a novel monoclonal antibody 692/29.

Abstract

Several monoclonal antibodies (mAbs) recognising Lewis(y), such as BR96, have reached the clinic but have failed to show good anti-tumour responses with an acceptable level of toxicity. No Lewis(b) mAbs have been trialled in patients. In this study we compare the specificity of three mAbs; BR96 (Lewis(y)), 2-25 LE (Lewis(b)) and 692/29 that recognises a unique facet of both Lewis(y) and Lewis(b). We then assessed the in vivo therapeutic effect of 692/29 using xenograft models.Using a glycan array, each mAb was shown to display a different binding pattern with only 692/29 binding to both Lewis(y) and Lewis(b). 692/29 was able to kill tumour cells over-expressing Lewis(y/b) directly, as well as by antibody and complement mediated cytotoxicity (ADCC/CDC), but failed to kill cells expressing low levels of these haptens. In contrast, BR96, directly killed cells expressing either high or low levels of Lewis(y) perhaps explaining its toxicity in patients. 2-25 LE failed to cause any direct killing but did mediate ADCC/CDC. Both 692/29 and BR96 bound to >80% of a panel of over 400 colorectal tumours whereas 2-25 LE showed lower reactivity (52%). 692/29 demonstrated more restricted normal tissue reactivity than both BR96 and 2-25 LE. 692/29 anti-Lewis(y/b) mAb also showed good in vivo killing in xenograft models.MAbs targeting both Lewis(y) and Lewis(b) may have a therapeutic advantage over mAbs targeting just one hapten. 692/29 has a more restricted normal tissue distribution and a higher antigen threshold for killing which should reduce its toxicity compared to a Lewis(y) specific mAb. 692/29 has an ability to directly kill tumours whereas the anti-Lewis(b) mAb does not. This suggests that Lewis(y) but not Lewis(b) are functional glycans. 692/29 showed good anti-tumour responses in vivo and is a strong therapeutic candidate.