Explore T-cell Bispecific Antibodies

Redirecting T cells to restore an immune response

Tumors can employ mechanisms that result in an insufficient supply of activated and/or antigen-specific T cells within the tumor microenvironment.1 One approach to countering these immuno-evasive mechanisms is to redirect and expand populations of T cells.2-4 Genentech is exploring this approach through the development of T-cell bispecific antibodies—a new generation of biologically engineered antibodies. T-cell bispecific antibodies are designed to simultaneously bind to T cells and tumor cell antigens, leading to T-cell activation, proliferation, and tumor cell death.5

Through Genentech's patented bispecific antibody design technologies, T cells can be physically recruited and linked to tumor surface antigens to elicit an antitumor immune response in patients with cancer.5 T-cell bispecific antibodies targeting a variety of tumor types have become an important component of Genentech's investigational cancer immunotherapy research.

Simultaneously binding to T cells and tumor cells

In contrast to early-generation therapeutic antibodies, T-cell bispecific antibodies combine the binding specificity of two antibodies in one molecule.2 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.4,5

Genentech's unique design technologies aim to optimize molecular structure


 

T-cell bispecific antibodies are engineered to have two or more distinct binding sites, allowing simultaneous binding to T cells and tumor surface antigens T-cell bispecific antibodies are engineered to have two or more distinct binding sites, allowing simultaneous binding to T cells and tumor surface antigens


CEA=carcinoembryonic antigen; Fab=fragment of antigen binding; Fc=fragment, crystallizable.

Molecular structure facilitates binding affinity

Genentech is exploring the potential of two innovative T-cell bispecific antibody structures to reinitiate an antitumor immune response across multiple tumor types.5,6
 

Monovalent and bivalent binding bispecific antibody structure Monovalent and bivalent binding bispecific antibody structure


Simultaneous 1:1 or 2:1 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 cross-linking, a junction formation between the T cell and tumor cell, and subsequent downstream signaling that leads to T-cell–mediated tumor killing through4,5

  • 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

T-cell bispecific-antibody–mediated tumor-cell killing does not require pre-existing immunity and may occur independently of T-cell specificity, activation, and differentiation status. Therefore, bispecific antibodies may be used to promote antitumor immune activity, while bypassing steps in the cancer immunity cycle.4,5,10,11

Genentech is exploring the potential of combining T-cell bispecific antibodies with other anticancer therapies, including PD-L1 inhibitors and antibody drug conjugates in the pursuit of enhancing T-cell–mediated cancer immunity.

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.12

Videos provided by Alex Ritter and Ira Mellman.

This compound and its use continues to be investigated in ongoing studies; efficacy and safety have not been established.

References

  1. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321-330. PMID: 28102259
  2. Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015;20:838-847. PMID: 25728220
  3. Frankel SR, Baeuerle PA. Targeting T cells to tumor cells using bispecific antibodies. Curr Opin Chem Biol. 2013;17:385-392. PMID: 23623807
  4. Bacac M, Klein C, Umana P. CEA TCB: a novel head-to-tail 2:1 T cell bispecific antibody for treatment of CEA-positive solid tumors. Oncoimmunology. 2016;5:e1203498. PMID: 27622073
  5. Bacac M, Fauti T, Sam J, et al. A novel carcinoembryonic antigen T-cell bispecific antibody (CEA TCB) for the treatment of solid tumors. Clin Cancer Res. 2016;22:3286-3297. PMID: 26861458
  6. Sun LL, Ellerman D, Mathieu M, et al. Anti-CD20/CD3 T cell–dependent bispecific antibody for the treatment of B cell malignancies. Sci Transl Med. 2015;7:287ra70. PMID: 25972002
  7. Klein C, Schaefer W, Regula JT. The use of CrossMAb technology for the generation of bi- and multispecific antibodies. mAbs. 2016;8:1010-1020. PMID: 27285945
  8. Klein C, Sustmann C, Thomas M, et al. Progress in overcoming the chain association issue in bispecific heterodimeric IgG antibodies. mAbs. 2012;4:653-663. PMID: 22925968
  9. Schaefer W, Regula JT, Bähner M, et al. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc Natl Acad Sci U S A. 2011;108:11187-11192. PMID: 21690412
  10. Davis MM. A new trigger for T cells. Cell. 2002;110:285-287. PMID: 12176315
  11. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. PMID: 23890059
  12. 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. PMID: 25228655