Abstract
Trop-2 has limited presence on normal tissues but is highly expressed in diverse epithelial cancers. (E1)-3s is a T-cell-redirecting trivalent bispecific antibody (bsAb), comprising an anti-CD3 scFv covalently linked to a stabilized dimer of a Trop-2-targeting Fab using Dock-and-Lock. We show for the first time that bsAb-mediated bidirectional trogocytosis occurs between target and T cells and involves immunologic synapses. We studied the effects of interferon-α (INFα) on (E1)-3s-mediated T-cell killing of human gastric and pancreatic cancer cell lines. T-cell activation, cytokine induction, and cytotoxicity were evaluated ex vivo using peripheral blood mononuclear cells (PBMC) or T cells with NCI-N87 gastric cancer as target cells. In vivo activity was assayed with NCI-N87 and Capan-1 (pancreatic) xenografts. In the presence of target cells and PBMCs, (E1)-3s did not cause excess cytokine production. When combined with (E1)-3s, peginterferonalfa-2a--which alone did not increase T-cell activation or raise cytokine levels over baseline--increased CD69 expression but did not significantly increase cytokine induction. (E1) 3s mediated a highly potent T-cell lysis of NCI-N87 target cells in vitro. Inclusion of peginterferonalfa-2a or a more potent form of INFα, 20*-2b, significantly potentiated the activity of (E1)-3s by more than 2.5- or 7-fold, respectively. In vivo, combining peginterferonalfa-2a with (E1)-3s delayed Capan-1 growth longer than each single agent. Similarly, combination therapy delayed tumor proliferation of NCI-N87 compared with (E1)-3s or peginterferonalfa-2a single-treatment groups. (E1)-3s effectively induced T-cell-mediated killing of Trop-2-expressing pancreatic and gastric cancers, which was enhanced with INFα.
Highlights
Various formats of bispecific antibodies engineered to redirect cytotoxic T cells, most often via CD3 binding, have demonstrated therapeutic efficacy in preclinical and clinical settings by binding tumor-associated antigens (TAA; ref. 1)
We demonstrate that IFNa enhanced the therapeutic efficacy of (E1)-3s without increasing the production of other cytokines to levels that could induce cytokine release syndrome (CRS)
We described the potential of the (X)-3s bispecific antibody (bsAb) format for redirecting T-cell–mediated therapy of both hematopoietic and solid tumors using several example constructs, including (E1)-3s, [19]-3s, and [20]-3s [18]
Summary
Various formats of bispecific antibodies (bsAb) engineered to redirect cytotoxic T cells, most often via CD3 binding, have demonstrated therapeutic efficacy in preclinical and clinical settings by binding tumor-associated antigens (TAA; ref. 1). Various formats of bispecific antibodies (bsAb) engineered to redirect cytotoxic T cells, most often via CD3 binding, have demonstrated therapeutic efficacy in preclinical and clinical settings by binding tumor-associated antigens Tandem scFvs consisting of an anti-CD3 and an anti-TAA domain, termed bispecific T-cell engagers (BiTE), have advanced the furthest, with two agents under clinical investigation [9]. MT110, the EpCAM (epithelial cell adhesion molecule) antibody xCD3 BiTE [12], is currently undergoing a phase I study in various solid tumors, including lung, gastric, colorectal, breast, prostate, and ovarian cancers (ClinicalTrials.gov identifier NCT00635596)
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