Data from FS118, a Bispecific Antibody Targeting LAG-3 and PD-L1, Enhances T-Cell Activation Resulting in Potent Antitumor Activity

Abstract

<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 (mAb<sup>2</sup>) 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 mAb<sup>2</sup>).</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 mAb<sup>2</sup> in blocking LAG-3- and PD-L1–mediated immune suppression and enhancing T-cell activity. In syngeneic tumor mouse models, mLAG-3/PD-L1 mAb<sup>2</sup> significantly suppressed tumor growth. Mechanistic studies revealed decreased LAG-3 expression on T cells following treatment with the mouse surrogate mLAG-3/PD-L1 mAb<sup>2</sup>, 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 mAb<sup>2</sup> 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>

Bispecific antibodies targeting immunomodulatory checkpoints for cancer therapy

“…Compared with individual blockade of PD-1 or LAG-3 signaling, MGD013 demonstrates a stronger capacity for T cell activation and cytokine secretion 52 . In syngeneic mouse models of colorectal cancer (CRC), FS118 enhances the antitumor immune response and decreases the expression of LAG-3 on T cells, which may be due to shedding of LAG-3 from the cell surface to serum 24,53,54 . Dendritic cells (DCs) can process and present TAAs, which are crucial in initiating the anti-tumor immune response.…”

“…Another phase I study reported that tebotelimab has promising early evidence of anti-tumor activity in relapsed or refractory diffuse large B-cell lymphoma with acceptable patient tolerance 99 . FS118 is a novel bsAb fusing LAG-3 binding sites into an anti-PD-L1 IgG1 antibody 24,54 . A phase I study involving FS118, first-in-human, was conducted to assess the safety and activity in patients with advanced malignancies 100 .…”