Development of an immune therapeutic approach against SARS-CoV-2

Immunotherapies are already successfully used for cancer treatment. In our lab two modular platform technologies were developed which demonstrated high success against various types of malignant cells: the universal chimeric antigen receptor (UniCAR) system, and the bispecific antibody (bsAb) based UniMAB system. Both approaches have the aim to recruit T cells to kill the malignant cells carrying a tumor associated antigen (TAA) on their surface. In the first case, UniCAR modified T cells are linked via a TAA specific target module (TM) to cancer cells. In the case of the UniMAB system, natural T cells are recruited to cancer cells via a TAA specific TM and a bsAb based effector module (EM) which binds to CD3 of T cells and to an epitope tag of the TM. In both cases, an immune complex is formed leading to T cell activation and tumor cell elimination. Most importantly, the T cell activation is dependent on the cross-linkage of T cells and tumor cells via the TM or TM/EM complex. Thus, T cell activation is steerable which increases the safety of these approaches. With the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading
to millions of deaths worldwide, we aimed to apply the UniCAR and UniMAB technology against SARS-CoV-2 and virus infected cells as novel immunotherapeutic treatment approach.
For this purpose, we designed two TMs binding to the receptor binding domain (RBD) of SARS-CoV-2. The first TM is based on a single chain fragment variable (scFv) with specificity for RBD, whereas the second one contains the extracellular domain of the human ACE2 receptor which is the entry receptor of SARS-CoV-2. Both TMs were able to efficiently recruit either UniCAR T cells or, in combination with the EM of the UniMAB system, natural T cells to efficiently kill human cells having the RBD of SARS-CoV-2 on their surface. Remarkably, the ACE2-Mb-TM is additionally able to block RBD/ACE2 interaction and potently neutralizes pseudo- as well as live SARS-CoV-2 which is even more pronounced when variants of concern are tested in these assays instead of the respective wild type. Thus, the ACE2-Mb TM represents a potent therapeutic drug against SARS-CoV-2, as it not only recruits UniCAR T cells and, in combination with the EM, natural T cells, but also neutralizes virus particles.