Despite advances with therapies targeting the programmed cell death protein 1 (PD-1) or its ligand (PD-L1), many cancer patients are refractory to or relapse following treatment. Resistance to anti-PD-1 treatment is associated with upregulation of other checkpoint inhibitor receptors such as LAG-3 (Lymphocyte Activation Gene 3). FS118, currently being evaluated in a Phase 1 clinical trial in patients with advanced malignancies (NCT03440437), is a tetravalent bispecific antibody targeting LAG-3 and PD-L1, two immune checkpoint molecules that promote tumour escape from immune surveillance. We have characterised both in vitro and in vivo the functional activity of FS118 and find that this bispecific antibody can overcome PD-L1 and LAG-3 immune suppressive signals. We report a potential novel mechanism of action not observed with the combination of single PD-L1 and LAG-3 antibodies. Our results indicate that FS118 represents a possible novel approach to overcome some of the mechanism of resistance to PD-(L)1 blockade.

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Whereas several important virulence factors in Escherichia coli O157 have been identified, studies suggest they are not always essential and are probably insufficient to account for the severe clinical manifestation of E. coli O157 infection. Identification of putative virulence determinants is crucial to the understanding of bacterial pathogenesis and genomic comparison analysis may aid the characterisation of unidentified virulence attributes. In this study, representational difference analysis (RDA) was used for genomic comparison of E. coli O157 with the proposed ancestral strain, E. coli O55. Unique E. coli O157 gene sequences were isolated and one, termed RDA-1, taken forward for further analysis. Southern blotting with labelled RDA-1 as a probe showed it to be present in 77% of E. coli O157 isolates and absent in all non-E. coli O157 screened. Sequence flanking RDA-1 was obtained from a genomic clone identified by hybridisation, and contained an open reading frame predicted to encode a novel iron-regulated outer membrane protein. ß

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<div>AbstractPurpose:<p>Although programmed death-ligand 1 (PD-L1) antibody–based therapy has improved the outcome of patients with cancer, acquired resistance to these treatments limits their clinical efficacy. FS118 is a novel bispecific, tetravalent antibody (mAb²) against human lymphocyte activation gene-3 (LAG-3) and PD-L1 with the potential to reinvigorate exhausted immune cells and overcome resistance mechanisms to PD-L1 blockade. Here, using FS118 and a murine surrogate, we characterized the activity and report a novel mechanism of action of this bispecific antibody.</p>Experimental Design:<p>This study characterizes the binding activity and immune function of FS118 in cell lines and human peripheral blood mononuclear cells and further investigates its antitumor activity and mechanism of action using a surrogate murine bispecific antibody (mLAG-3/PD-L1 mAb²).</p>Results:<p>FS118 demonstrated simultaneous binding to LAG-3 and PD-L1 with high affinity and comparable or better activity than the combination of the single component parts of the mAb² in blocking LAG-3- and PD-L1–mediated immune suppression and enhancing T-cell activity. In syngeneic tumor mouse models, mLAG-3/PD-L1 mAb² significantly suppressed tumor growth. Mechanistic studies revealed decreased LAG-3 expression on T cells following treatment with the mouse surrogate mLAG-3/PD-L1 mAb², whereas LAG-3 expression increased upon treatment with the combination of mAbs targeting LAG-3 and PD-L1. Moreover, following binding of mLAG-3/PD-L1 mAb² to target-expressing cells, mouse LAG-3 is rapidly shed into the blood.</p>Conclusions:<p>This study demonstrates a novel benefit of the bispecific approach over a combination of mAbs and supports the further development of FS118 for the treatment of patients with cancer.</p></div>