And more on the second poster presentation...23 Sep 2022 09:24
PRESENTER: Ruhul Choudhury
GlyMabs, glycome-targeting monoclonal antibodies for cancer therapy
Ruhul Choudhury, Scancell Ltd
Glycosylation is key in regulating various cellular functions. Aberrant glycosylation plays a significant role in cancer. Current understanding of glycosylation in cancer research have unravelled potential biologics targeting cancer-associated glycans. This unmet need led to Scancell’s GlyMab platform of four monoclonal antibodies (mAbs) targeting glycans on lipids and/or proteins. SC129 targets highly expressed Sialyl-di-lewisa glycan in pancreatic tumour tissue, as well as other forms of cancer, with limited expression on normal human tissue. SC129 targets approximately 85% of pancreatic tumours, with 65.79% showing strong target expression (HS>150), 7.89% moderate binding (HS>50-150) and 13.16% weak binding (HS>5-50). In vitro studies demonstrated antibody-drug conjugate (ADC) for SC129 conjugated with auristatin E or maytansinoids showed (sub)nanomolar potency for colorectal and pancreatic cancer cell lines (1). This coincided with a significant anti-tumour effect in an in vivo COLO205 xenograft model indicating that SC129 has potential to be used for cancer treatment as an ADC.
SC88 targets LecLex, di-Lea, and LeaLex, as well as Lea-containing glycans. This mAb showed strong binding at 64.29%,
28.57% moderate binding and 7.14% weak binding to colorectal tumours. SC88 exhibits strong effector functions (ADCC and CDC) in addition to direct tumour cell killing via a caspase-independent mechanism (2).
SC134 specifically targets Fuca1-2Galß1-3GalNAcß1-4(Neu5Aca2-3)Galß1-4Glc-ceramide. This glycolipid is highly expressed in small cells lung carcinoma (SCLC). The absence of healthy tissue binding suggests SC134 may redirect T cells in T cell redirecting bispecific format. SC134 shows strong internalising capabilities in SCLC cell lines and delivers DNA-modifying drugs with subnanomolar efficiency, rendering it a viable candidate for ADC development.
The humanised leads for SC129, SC88 and SC134 candidates recapitulates their parental mAb in their binding and functional characteristics. SC27, our ultraspecific Lewisy mAb binds to a wide range of cancers, additionally, this mAb has superb internalising ability combined with drug delivery to the lysosomes indicating potential for ADC use.
In summary, Scancell’s Glymabs are highly specific for a broad range of cancers making them viable candidates for cancer therapeutics.
References
1. Tivadar ST, McIntosh RS, Chua JX, Moss R, Parsons T, Zaitoun AM, et al. Monoclonal Antibody Targeting Sialyl-di-Lewis(a)- Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential. Mol Cancer Ther. 2020;19(3):790-801.
2. Chua JX, Vankemmelbeke M, McIntosh RS, Clarke PA, Moss R, Parsons T, et al. Monoclonal Antibodies Targeting LecLexRelated Glycans with Potent Antitumor Activity. Clin Cancer Res. 2015;21(13):2963-74.
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