CD18 Antibody Application Blocks Unwanted Off-Target T Cell Activation Caused by Bispecific Antibodies

SIMPLE SUMMARY: Bispecific antibodies are a very effective immunotherapy against different types of cancer since they activate T cells in the presence of tumor cells. However, they can cause severe side effects, such as a systemic inflammation called cytokine release syndrome. We aimed to clarify an important mechanism that causes cytokine release syndrome. In cocultures of T cells with endothelial cells or lymphoid cells, application of bispecific antibodies can induce T cell activation and cytokine release in the absence of tumor cells. By blocking the adhesion molecule CD18, this interaction is interrupted and the unwanted T cell activation is diminished. CD18 blockade, however, does not interfere with T cell activation when tumor cells are present. Therefore, CD18 blockade could prevent side effects of bispecific antibodies without decreasing the anti-tumor effect. ABSTRACT: T cell-recruiting bispecific antibodies (bsAbs) are successfully used for the treatment of cancer. However, effective treatment with bsAbs is so far hampered by severe side effects, i.e., potentially life-threatening cytokine release syndrome. Off-target T cell activation due to binding of bispecific CD3 antibodies to T cells in the absence of target cells may contribute to excessive cytokine release. We report here, in an in vitro setting, that off-target T cell activation is induced by bsAbs with high CD3 binding affinity and increased by endothelial- or lymphoid cells that act as stimulating bystander cells. Blocking antibodies directed against the adhesion molecules CD18/CD54 or CD2/CD58 markedly reduced this type of off-target T cell activation. CD18 blockade—in contrast to CD2—did not affect the therapeutic activity of various bsAbs. Since CD18 antibodies have been shown to be safely applicable in patients, blockade of this integrin holds promise as a potential target for the prevention of unwanted off-target T cell activation and allows the application of truly effective bsAb doses.