Therapeutic Targeting of Lewis ^y and Lewis ^b with a Novel Monoclonal Antibody 692/29

Abstract

Background

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.

Methodology/Principal Findings

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.

Conclusions/Significance

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.