Bispecific Antibody Format and the Organization of Immunological Synapses in T Cell-Redirecting Strategies for Cancer Immunotherapy

Abstract

T cell-redirecting strategies have emerged as effective cancer immunotherapy approaches. Bispecific antibodies (bsAbs) are designed to specifically recruit T cells to the tumor microenvironment and induce the assembly of the immunological synapse (IS) between T cells and cancer cells or antigen-presenting cells. The way that the quality of the IS might predict the effectiveness of T cell-redirecting strategies, including those mediated by bsAbs or by chimeric antigen receptors (CAR)-T cells, is currently under discussion. Here we review the organization of the canonical IS assembled during natural antigenic stimulation through the T cell receptor (TCR) and to what extent different bsAbs induce T cell activation, canonical IS organization, and effector function. Then, we discuss how the biochemical parameters of different formats of bsAbs affect the effectivity of generating an antigen-induced canonical IS. Finally, the quality of the IS assembled by bsAbs and monoclonal antibodies or CAR-T cells are compared, and strategies to improve bsAb-mediated T cell-redirecting strategies are discussed.

Keywords: CAR; IS; T cell; TCR; bsAb; immunotherapy.

Figure 1

Immunological synapse assembled in response to antigen or bsAbs. (A) Schematic of the canonical IS assembled between a T cell and an APC presenting an antigenic peptide bound to the major histocompatibility complex (pMHC). pMHC I and II are indicated. However, for clarity, it is only represented the MHC class I. The main activating molecules, cytoskeleton components, and secretory granules or cytokines delivered at the contact interface are depicted in the upper panel. The principal components of the cSMAC, pSMAC, and dSMAC are indicated in the lower schematic. The signaling domain located in the cSMAC contains TCR microclusters (MCs), co-stimulation molecules such as CD28 and PKCθ. The secretory domain of the cSMAC secretes perforin- and granzyme-containing granules in the IS assembled by cytotoxic T cells and different types of cytokines in the IS assembled by helper T cells. (B) Schematic of the topology of the IS assembly induced by bsAbs between a T cell and a tumor cell. BsAbs typically engage the T cell by the CD3ε chain of the TCR and the tumor cell through a TAA. This leads to the establishment of antigen-stimulated canonical IS. Upper panel shows the main elements of the IS induced by bsAbs. The cSMAC, pSMAC, and dSMAC compositions are represented in the lower schematic. The signaling domain located in the cSMAC contains TCR MCs and signaling proteins such as PKCθ. Secretory domain of the cSMAC secretes lytic granules containing perforin and granzyme B.