About Bispecific Antibodies
Redirecting T cells to restore an immune response
Tumors can employ mechanisms that alter the immune response in their microenvironment.1 One approach to countering these immuno-evasive mechanisms is to redirect and expand populations of T cells.2,3 T cells can be physically recruited and linked to tumor surface antigens to elicit an antitumor immune response in patients with cancer.4 Bispecific antibodies are designed to simultaneously bind to T cells and tumor cell antigens, leading to T-cell activation, proliferation, and tumor cell death.4
Simultaneously binding to T cells and tumor cells
Bispecific antibodies targeting a variety of tumor types have become an important component of Genentech's investigational cancer immunotherapy research. In contrast to early-generation therapeutic antibodies, bispecific antibodies combine the binding specificity of two antibodies in one molecule.5 They are engineered to have two or more distinct Fab regions (antigen-binding sites) with a common Fc region. This structure allows simultaneous binding to CD3 on T cells and target antigens on tumor cells, which brings the T cells into close proximity with the target tumor cells, leading to T-cell–mediated killing of the tumor cells.3,4
Bispecific antibody structure
CEA=carcinoembryonic antigen; Fab=fragment of antigen binding; Fc=fragment, crystallizable.
Variety of molecular structures for robust T-cell anticancer strategies
We are exploring the potential of innovative bispecific antibody structures that activate T cells to induce an antitumor immune response across multiple tumor types.5,6
Simultaneous binding of a T-cell bispecific antibody to CD3 on T cells and a tumor cell surface antigen, such as CEA or CD20, may result in the formation of an immune synapse, a junction formation between the T cell and tumor cell, and subsequent downstream signaling that may lead to T-cell–mediated tumor killing through:3,4
- T-cell activation and secretion of cytotoxic granules
- Secretion of cytokines/chemokines that generate a pro-inflammatory tumor microenvironment and recruit additional T cells
- T-cell proliferation and expansion at the tumor site
We are exploring the potential of combining T-cell bispecific
antibodies with other anticancer therapies, including
PD-L1 inhibition and antibody drug
conjugates in the pursuit of enhancing T-cell–mediated
T-cell bispecific antibodies in action
Watch a time-lapse microscope video of the T-cell bispecific antibody in activating cytotoxic T lymphocytes designed to kill tumor cells. As demonstrated in preclinical models, upon dispersion of T-cell bispecific antibodies, the cytotoxic T cells (seen in red) immediately recognize and begin to destroy the target cancer cells (seen in blue). Green flashes in the tumor cells indicate imminent T-cell–induced cell death.8
This compound and its use continue to be investigated in ongoing studies; efficacy and safety have not been established.
- Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321-330.
- Frankel SR, Baeuerle PA. Targeting T cells to tumor cells using bispecific antibodies. Curr Opin Chem Biol. 2013;17:385-392.
- Bacac M, Klein C, Umana P. Oncoimmunology. 2016;5:e1203498.
- Bacac M, Fauti T, Sam J, et al. Clin Cancer Res. 2016;22:3286-3297.
- Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015;20:838-847.
- Sun LL, Ellerman D, Mathieu M, et al. Sci Transl Med. 2015;7:287ra70.
- Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10.
- Junttila TT, Li J, Johnston J, et al. Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells. Clin Cancer Res. 2014;74:5561-5571.