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|Ref Type||Journal Article|
|Authors||Shaw SM, Middleton J, Wigglesworth K, Charlemagne A, Schulz O, Glossop MS, Whalen GF, Old R, Westby M, Pickford C, Tabakman R, Carmi-Levy I, Vainstein A, Sorani E, Zur AA, Kristian SA|
|Title||AGI-134: a fully synthetic α-Gal glycolipid that converts tumors into in situ autologous vaccines, induces anti-tumor immunity and is synergistic with an anti-PD-1 antibody in mouse melanoma models.|
|Journal||Cancer cell international|
|Abstract Text||Treatments that generate T cell-mediated immunity to a patient's unique neoantigens are the current holy grail of cancer immunotherapy. In particular, treatments that do not require cumbersome and individualized ex vivo processing or manufacturing processes are especially sought after. Here we report that AGI-134, a glycolipid-like small molecule, can be used for coating tumor cells with the xenoantigen Galα1-3Galβ1-4GlcNAc (α-Gal) in situ leading to opsonization with pre-existing natural anti-α-Gal antibodies (in short anti-Gal), which triggers immune cascades resulting in T cell mediated anti-tumor immunity.Various immunological effects of coating tumor cells with α-Gal via AGI-134 in vitro were measured by flow cytometry: (1) opsonization with anti-Gal and complement, (2) antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells, and (3) phagocytosis and antigen cross-presentation by antigen presenting cells (APCs). A viability kit was used to test AGI-134 mediated complement dependent cytotoxicity (CDC) in cancer cells. The anti-tumoral activity of AGI-134 alone or in combination with an anti-programmed death-1 (anti-PD-1) antibody was tested in melanoma models in anti-Gal expressing galactosyltransferase knockout (α1,3GT-/-) mice. CDC and phagocytosis data were analyzed by one-way ANOVA, ADCC results by paired t-test, distal tumor growth by Mantel-Cox test, C5a data by Mann-Whitney test, and single tumor regression by repeated measures analysis.In vitro, α-Gal labelling of tumor cells via AGI-134 incorporation into the cell membrane leads to anti-Gal binding and complement activation. Through the effects of complement and ADCC, tumor cells are lysed and tumor antigen uptake by APCs increased. Antigen associated with lysed cells is cross-presented by CD8α+ dendritic cells leading to activation of antigen-specific CD8+ T cells. In B16-F10 or JB/RH melanoma models in α1,3GT-/- mice, intratumoral AGI-134 administration leads to primary tumor regression and has a robust abscopal effect, i.e., it protects from the development of distal, uninjected lesions. Combinations of AGI-134 and anti-PD-1 antibody shows a synergistic benefit in protection from secondary tumor growth.We have identified AGI-134 as an immunotherapeutic drug candidate, which could be an excellent combination partner for anti-PD-1 therapy, by facilitating tumor antigen processing and increasing the repertoire of tumor-specific T cells prior to anti-PD-1 treatment.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|AGI-134||AGI 134|AGI134|aGal AGI-134|Alpha-Gal AGI-134||AGI-134 is a synthetic glycolipid consisting of an alpha-Gal trisaccharide and lipid tail, which potentially induces cytotoxicity and leads to tumor regression (PMID: 31889898).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||melanoma||not applicable||AGI-134||Preclinical||Actionable||In a preclinical study, AGI-134 treatment induced tumor regression, reduced formation of secondary lesions and increased survival in mouse models of melanoma (PMID: 31889898).||31889898|
|Unknown unknown||lung carcinoma||not applicable||AGI-134||Preclinical - Cell culture||Actionable||In a preclinical study, AGI-134 treatment induced cell death of lung carcinoma cells in the presence of normal human serum in culture and induced phagocytosis when co-cultured with human macrophages (PMID: 31889898).||31889898|
|Unknown unknown||colon adenocarcinoma||not applicable||AGI-134||Preclinical - Cell culture||Actionable||In a preclinical study, AGI-134 treatment induced cell death of colon adenocarcinoma cells in the presence of normal human serum in culture (PMID: 31889898).||31889898|