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Significance Statement
The recent FDA approval of dinutuximab (Unituxin) for high-risk pediatric neuroblastoma and ongoing clinical trials with anti-ganglioside (glycolipid) mAbs pave the way for other glycolipid-targeting antibodies (mAbs) in cancer therapy.
Cancer cell associated glycans constitute excellent targets for therapeutic antibody development as they are differentially expressed compared to healthy cells and influence a wide range of cell biological processes. Recent advances in tumor glycomic analyses have highlighted the dramatic alterations in the cellular glycome of cancer tissues. Glycans represent a major challenge however, as they are weakly immunogenic often generating low affinity IgM mAbs with limited clinical value.
We have succeeded in generating two high (subnanomolar) functional affinity anti-Lewis (Le) glycan IgG mAbs, via liposome-based immunizations, that target glycolipid and glycoproteins on a range of tumor tissues with limited normal tissue cross-reactivity. Over 50% of colorectal, pancreatic and gastric tumor tissues expressed the Lec/Lea – glycoepitope, with high expression being an independent prognostic marker associated with poor survival in colorectal cancer.
The mAbs exhibited excellent immune effector (ADCC and CDC) functions as well as a direct cytotoxic effect on high glycoepitope – expressing tumor cell lines which involved cellular aggregation, pore formation and eventual cell death via a mechanism reminiscent of oncotic necrosis with potential for adaptive immunity engagement. Importantly, these favorable in vitro attributes led to a significant reduction in tumor burden and survival benefit in vivo, in a mouse metastatic colorectal xenograft model. Finally, their efficient internalization and delivery of indirectly conjugated toxin to lysosomal compartments highlights their potential for drug carrier development.
We envisage that our Lewis glycan mAbs with their multimodal cancer cell targeting activities will translate into therapeutic anti-tumor efficacy in a clinical setting.
About the Authors
Prof. Lindy Durrant holds a Chair in Cancer Immunotherapy and recently established the Nottingham University Therapeutic Antibody Centre (NUTAC) whose main focus is to develop therapeutic anti-cancer antibodies. Prof Durrant is also joint CEO and CSO of Scancell Ltd., a cancer vaccines biotech company.
Mireille Vankemmelbeke is a senior postdoctoral fellow at NUTAC. Her research interests encompass therapeutic antibodies and cancer immunotherapy.
Jia Xin Chua carried out her postgraduate work in Prof. Durrant’s group and her current research interests involve generating novel glycolipid antibodies with anti-tumor activity.
Journal Reference
Clin Cancer Res. 2015;21(13):2963-74.
Chua JX1, Vankemmelbeke M1, McIntosh RS1, Clarke PA2, Moss R1, Parsons T1, Spendlove I1, Zaitoun AM3, Madhusudan S1, Durrant LG4.
[expand title=”Show Affiliations”]- Division of Cancer and Stem Cells, School of Medicine, City Hospital Campus, University of Nottingham, Nottingham, United Kingdom.
- Division of Cancer and Stem Cells, School of Medicine, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom.
- Section of Surgery, School of Medicine, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom.
- Division of Cancer and Stem Cells, School of Medicine, City Hospital Campus, University of Nottingham, Nottingham, United Kingdom. [email protected].
Abstract
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 Le(c)Le(x), di-Le(a), and Le(a)Le(x), as well as Le(a)-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 glyco-epitope 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 caspase-independent 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.
©2015 American Association for Cancer Research.
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