Therapeutic Targeting of Lewisy and Lewisb with a Novel Monoclonal Antibody 692/29

Abstract

BackgroundSeveral monoclonal antibodies (mAbs) recognising Lewisy, such as BR96, have reached the clinic but have failed to show good anti-tumour responses with an acceptable level of toxicity. No Lewisb mAbs have been trialled in patients. In this study we compare the specificity of three mAbs; BR96 (Lewisy), 2-25 LE (Lewisb) and 692/29 that recognises a unique facet of both Lewisy and Lewisb. We then assessed the in vivo therapeutic effect of 692/29 using xenograft models.Methodology/Principal FindingsUsing a glycan array, each mAb was shown to display a different binding pattern with only 692/29 binding to both Lewisy and Lewisb. 692/29 was able to kill tumour cells over-expressing Lewisy/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 Lewisy 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-Lewisy/b mAb also showed good in vivo killing in xenograft models.Conclusions/SignificanceMAbs targeting both Lewisy and Lewisb 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 Lewisy specific mAb. 692/29 has an ability to directly kill tumours whereas the anti-Lewisb mAb does not. This suggests that Lewisy but not Lewisb are functional glycans. 692/29 showed good anti-tumour responses in vivo and is a strong therapeutic candidate.