Neutralizing antibodies exert a potent inhibitory effect on viral entry; however, they are less effective in therapeutic models than in prophylactic models, presumably because of their limited efficacy in eliminating virus-producing cells via Fc-mediated cytotoxicity. Herein, we present a SARS-CoV-2 spike-targeting bispecific T-cell engager (S-BiTE) strategy for controlling SARS-CoV-2 infection. This approach blocks the entry of free virus into permissive cells by competing with membrane receptors and eliminates virus-infected cells via powerful T cell-mediated cytotoxicity. S-BiTE is effective against both the original and Delta variant of SARS-CoV2 with similar efficacy, suggesting its potential application against immune-escaping variants. In addition, in humanized mouse model with live SARS-COV-2 infection, S-BiTE treated mice showed significantly less viral load than neutralization only treated group. The S-BiTE strategy may have broad applications in combating other coronavirus infections.

Purpose: To evaluate the potential added value of integrating anti-apoptotic molecules for improving the anti-tumor activity of CAR-T cells. Methods: Four small molecules inhibiting apoptosis were tested for their ability to prevent activated induced CAR-T cell death. Five CD20-targeting, CD137 (4-1BB) and CD3ζ integrated CAR-T cells (20BBZ) with constitutively expressed anti-apoptotic genes were established, and we screened out the strongest proliferation enhancer: Bcl-2. The memory subtype and the exhaustion markers of CAR-T cells were analyzed. The anti-tumor activities of Bcl-2 integrating CAR-T cells (20BBZ-Bcl-2) were evaluated in vitro and in a mouse xenograft lymphoma model. Conclusion: The 20BBZ-Bcl-2 CAR-T cells showed improved proliferation ability compared to 20BBZ CAR-T cells in vitro. In addition, activation-induced apoptosis was reduced in the 20BBZ-Bcl-2 CAR-T cells. Consistent with the enhanced proliferation in vitro, 20BBZ-Bcl-2 CAR-T cells exhibited improved anti-tumor activity in a mouse xenograft lymphoma model.

The emergence of the novel human severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to the pandemic of coronavirus disease 2019 (COVID-19), which has markedly affected global health and the economy. Both uncontrolled viral replication and a proinflammatory cytokine storm can cause severe tissue damage in patients with COVID-19. SARS-CoV-2 utilizes angiotensin-converting enzyme 2 (ACE2) as its entry receptor. In this study, we generated ACE2 extracellular domain-Fc and single-chain variable fragment-interleukin 6 (IL-6) single-chain variable fragment against IL-6 receptor (scFv-IL6R)-Fc fusion proteins to differentially neutralize viruses and ameliorate the cytokine storm. The human ACE2 (hACE2)1-740-Fc fusion protein showed a potent inhibitory effect on pseudo-typed SARS-CoV-2 entry and a good safety profile in mice. In addition, scFv-IL6R-Fc strongly blocked IL-6 signal activation. We also established a mesenchymal stromal cell (MSC)-based hACE21-740-Fc and scFv-IL6R-Fc delivery system, which could serve as a potential therapy strategy for urgent clinical needs of patients with COVID-19.