Posts in Category: Technology - AvidiMab

Engineering the human Fc-region enables direct cell killing by cancer glycan-targeting antibodies without the need for immune effector cells or complement

Fc-engineering cytotoxicity in cancer glycan-targeting mAbs

Engineering the human Fc-region enables direct cell killing by cancer glycan-targeting antibodies without the need for immune effector cells or complement

Mireille Vankemmelbeke, Richard S. McIntosh, Jia Xin Chua, Thomas Kirk, Ian Daniels, Marilena Patsalidou, Robert Moss, Tina Parsons, David Scott, Gemma Harris, Judith M. Ramage, Ian Spendlove and Lindy G. Durrant

ABSTRACT: Murine IgG3 glycan-targeting mAb often induces direct cell killing in the absence of immune effector cells or complement via a proinflammatory mechanism resembling oncotic necrosis. This cancer cell killing is due to non-covalent association between Fc regions of neighboring antibodies, resulting in enhanced avidity. Human isotypes do not contain the residues underlying this cooperative binding mode; consequently, the direct cell killing of mouse IgG3 mAb is lost upon chimerization or humanization. Using the Lewisa/c/x -targeting 88mAb, we identified the murine IgG3 residues underlying the direct cell killing and increased avidity via a series of constant region shuffling and subdomain swapping approaches to create improved ('i') chimeric mAb with enhanced tumor killing in vitro and in vivo. Constant region shuffling identified a major CH3 and a minor CH2 contribution, which was further mapped to discontinuous regions among residues 286-306 and 339-378 that, when introduced in 88hIgG1, recapitulated the direct cell killing and avidity of 88mIgG3. Of greater interest was the creation of a sialyl-di-Lewisa -targeting i129G1 mAb via introduction of these selected residues into 129hIgG1, converting it into a direct cell killing mAb with enhanced avidity and significant in vivo tumor control. The human iG1 mAb, termed Avidimabs, retained effector functions, paving the way for the proinflammatory direct cell killing to promote ADCC and CDC through relief of immunosuppression. Ultimately, Fc engineering of human glycan-targeting IgG1 mAb confers proinflammatory direct cell killing and enhanced avidity, an approach that could be used to improve the avidity of other mAb with therapeutic potential.

 

Monoclonal Antibody Targeting Sialyl-di-Lewisa– Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential

Monoclonal Antibody Targeting Sialyl-di-Lewisa – Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential

Silvana T. Tivadar, Richard S. McIntosh, Jia Xin Chua, Robert Moss, Tina Parsons, Abed M. Zaitoun, Srinivasan Madhusudan, Lindy G. Durrant and Mireille Vankemmelbeke

ABSTRACT: Tumor glycans constitute attractive targets for therapeutic antibodies. The sialylated glycocalyx plays a prominent role in cancer progression and immune evasion. Here, we describe the characterization of the mAb, FG129, which targets tumor-associated sialylated glycan, and demonstrate its potential for multimodal cancer therapy. FG129, obtained through BALB/c mouse immunizations with liposomes containing membrane glycan extracts from the colorectal cancer cell line LS180, is an mIgG1k that targets sialyl-di-Lewisa–containing glycoproteins. FG129, as well as its chimeric human IgG1 variant, CH129, binds with nanomolar functional affinity to a range of colorectal, pancreatic, and gastric cancer cell lines. FG129 targets 74% (135/182) of pancreatic, 50% (46/92) of gastric, 36% (100/281) of colorectal, 27% (89/327) of ovarian, and 21% (42/201) of non–small cell lung cancers, by IHC. In our pancreatic cancer cohort, high FG129 glyco-epitope expression was significantly associated with poor prognosis (P ¼ 0.004). Crucially, the glyco-epitope displays limited normal tissue distribution, with FG129 binding weakly to a small percentage of cells within gallbladder, ileum, liver, esophagus, pancreas, and thyroid tissues. Owing to glyco-epitope internalization, we validated payload delivery by CH129 through monomethyl auristatin E (MMAE) or maytansinoid (DM1 and DM4) conjugation. All three CH129 drug conjugates killed high-binding colorectal and pancreatic cancer cell lines with (sub)nanomolar potency, coinciding with significant in vivo xenograft tumor control by CH129-vcMMAE. CH129, with its restricted normal tissue distribution, avid tumor binding, and efficient payload delivery, is a promising candidate for the treatment of sialyl-di-Lewisa– expressing solid tumors, as an antibody–drug conjugate or as an alternative cancer immunotherapy modality.

CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference : Translating Science into Survival 2018

CRI 2018 : Post translationally modified homocitrulline induced by MDSCs can be an effective anti-tumour target for CD4 T cells

K. Cook, W. Xue, P. Symonds, M. Gijon, P. Vaghela, R. Choudhury, S. Shah, S. Atabani, R. Metheringham, V. Brentville, L. Durrant 

CRI 2018 : Pre-existing citrulline specific CD4 T cells can be efficiently harnessed for tumour therapy

V. Brentville, P. Symonds, K. Cook, I. Daniels, S. Atabani, R. Choudhury, P. Vaghela, R. Metheringham, M. Gijon, W. Xue, L. Durrant

CRI 2018 : Targeting gastrointestinal tumors with constant region-engineered anti-glycan antibodies

M. Vankemmelbeke, T. Kirk, C. Papagregoriou, S. Aziz, J.X. Chua, R.S. McIntosh, L.G. Durrant