Monoclonal antibodies targeting LecLex-related glycans with potent antitumor activity

Chua, Jiaxin; Vankemmelbeke, Mireille; McIntosh, Richard S.; Clarke, Philip A.; Moss, Robert; Parsons, Tina; Spendlove, Ian; Zaitoun, Abid M.; Madhusudan, Srinivasan; Durrant, Lindy

Abstract

© 2015 American Association for Cancer Research. Purpose: To produce antitumor monoclonal antibodies (mAbs) targeting glycans as they are aberrantly expressed in tumors and are coaccessory molecules for key survival pathways. Experimental Design: Two mAbs (FG88.2 and FG88.7) recognizing novel tumor-associated Lewis (Le) glycans were produced by immunizations with plasma membrane lipid extracts of the COLO205 cell line. Results: Glycan array analysis showed that both mAbs bound LecLex, di-Lea, and LeaLex, as well as Lea-containing glycans. These glycans are expressed on both lipids and proteins. Both mAbs showed strong tumor reactivity, binding to 71% (147 of 208) of colorectal, 81% (155 of 192) of pancreatic, 54% (52 of 96) of gastric, 23% (62 of 274) of non-small cell lung, and 31% (66 of 217) of ovarian tumor tissue in combination with a restricted normal tissue distribution. In colorectal cancer, high FG88 glycoepitope expression was significantly associated with poor survival. The mAbs demonstrated excellent antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), in addition to direct tumor cell killing via a caspaseindependent mechanism. Scanning electron microscopy revealed antibody-induced pore formation. In addition, the mAbs internalized, colocalized with lysosomes, and delivered saporin that killed cells with subnanomolar potency. In vivo, the mAbs demonstrated potent antitumor efficacy in a metastatic colorectal tumor model, leading to significant long-term survival. Conclusions: The mAbs direct and immune-assisted tumor cell killing, pan-tumor reactivity, and potent in vivo antitumor efficacy indicate their potential as therapeutic agents for the treatment of multiple solid tumors. In addition, internalization of saporin conjugates and associated tumor cell killing suggests their potential as antibody drug carriers.

Citation

Chua, J., Vankemmelbeke, M., McIntosh, R. S., Clarke, P. A., Moss, R., Parsons, T., Spendlove, I., Zaitoun, A. M., Madhusudan, S., & Durrant, L. (2015). Monoclonal antibodies targeting LecLex-related glycans with potent antitumor activity. Clinical Cancer Research, 21(13), 2963-2974. https://doi.org/10.1158/1078-0432.CCR-14-3030

• Journal Article Type: Article
• Acceptance Date: Feb 28, 2015
• Online Publication Date: Mar 16, 2015
• Publication Date: Jul 1, 2015
• Deposit Date: May 29, 2018
• Journal: Clinical Cancer Research
• Print ISSN: 1078-0432
• Electronic ISSN: 1557-3265
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 21
• Issue: 13
• Pages: 2963-2974
• DOI: https://doi.org/10.1158/1078-0432.CCR-14-3030
• Public URL: https://nottingham-repository.worktribe.com/output/1111519
• Publisher URL: http://clincancerres.aacrjournals.org/content/21/13/2963
• Related Public URLs: https://www.scopus.com/inward/record.uri?eid=2-s2.0-84941952024&partnerID=40&md5=2b9aa422b43042c7932fbc8fc95ff847