Bridging the gap with multispecific immune cell engagers in cancer and infectious diseases

Abstract

By binding to multiple antigens simultaneously, multispecific antibodies are expected to substantially improve both the activity and long-term efficacy of antibody-based immunotherapy. Immune cell engagers, a subclass of antibody-based constructs, consist of engineered structures designed to bridge immune effector cells to their target, thereby redirecting the immune response toward the tumor cells or infected cells. The increasing number of recent clinical trials evaluating immune cell engagers reflects the important role of these molecules in new therapeutic approaches for cancer and infections. In this review, we discuss how different immune cell types (T and natural killer lymphocytes, as well as myeloid cells) can be bound by immune cell engagers in immunotherapy for cancer and infectious diseases. Furthermore, we explore the preclinical and clinical advancements of these constructs, and we discuss the challenges in translating the current knowledge from cancer to the virology field. Finally, we speculate on the promising future directions that immune cell engagers may take in cancer treatment and antiviral therapy.

Keywords: Cancer; Immune cell engagers; Immunotherapy; Multispecific antibodies; Virus.

Fig. 1

Structures of monoclonal antibodies. VH variable heavy chain, VL variable light chain, CH constant heavy chain, CL constant light chain, Fab fragment antigen binding, Fc fragment crystallizable. Created with Biorender

Fig. 2

Various T-cell engager (TCE) formats described in immuno-oncology. Single-chain variable fragments (scFvs) derived from T-cell receptor antibodies (blue) and from tumor-associated antigen antibodies (red) can associate to form bispecific T-cell engagers (BiTEs). BiTEs can be combined with a third scFv (green) to form a trispecific T-cell engager (TriTE) and with an additional moiety to form a tetraspecific T-cell engager (TetraTE). BiTEs can also be complemented with the extracellular domain of PD1 to form a checkpoint inhibitor T-cell engager (CiTE) or administered with a second molecule, such as an anti-CD28 × anti-PDL1, as in the simultaneous multiple interaction T-cell engager (SMiTE). Various molecular modifications, such as mutations of the VH-VL interface, shorter links between domains and the addition of disulfide bonds, have led to the development of additional formats, such as diabody, tandem diabody and dual affinity retargeting (DART). Created with Biorender

Fig. 3

T-cell engagers described in viral diseases. DART dual affinity retargeting, HBSAg hepatitis B surface antigen. Created with Biorender

Fig. 4

Overview of NK-cell engagers (NKCEs) in cancer. NKCEs are generally composed of single-chain variable fragments (scFvs) or specific ligands directed against i) NK cell targets such as CD16a (purple), IL-15R (blue and purple), NKp46 (green), NKp30 (yellow), NKG2C (pink) or CD122 (dark blue), and ii) tumor-associated antigens such as CD33 (red), CD30 (green), EpCAM (yellow and orange), CD133 (dark blue), EGFR (light green), BCMA (pink), HER2 (light purple) or CD123 (light yellow). BiKE bispecific killer engager, TriKE trispecific killer engager, TetraKE tetraspecific killer engager, EGFR epidermal growth factor receptor, BCMA B-cell maturation antigen, HER2 receptor protein tyrosine kinase erbB-2, TEM8 tumor endothelial marker 8, CLEC12 C-type lectin domain family 12 member A, IL-15R IL-15 receptor, IL-2v IL-2 variant. Created with Biorender

Fig. 5

NK cell engagers targeting HIV-infected T cells. Bispecific killer engagers (BiKEs), dual affinity retargeting (DART) proteins or gold (Au) nanoparticles are targeted against NK cells via CD16a and against HIV-infected T cells via anti-gp41/anti-gp120 binding moieties. Created with Biorender