Harnessing the power of the immune system: from bispecific antibodies to CAR-Ts and beyond

by Diane Seimetz

T cells are known as the most potent killer cells of the immune system, designed by nature to prevent unwanted challenges. The first class of therapeutic products harnessing the power of T cells for target-specific treatment of oncological diseases was bispecific antibodies. The first T-cell engaging bispecific antibodies that obtained approval were catumaxomab [1] and blinatumomab [2].

Eight years later, the first autologous chimeric antigen receptor (CAR)-T cells received regulatory approval [3]. CAR-T cells are the cellular interpretation of T-cell engaging therapies and have shown remarkable clinical results.

While building on the successes seen with CAR-Ts, further developments are ongoing to address issues related to manufacturability and cost of goods, improve safety and efficacy as well as exploring additional targets and further technologies for genetic modification. One approach to enhance the technology is allogeneic CAR-T or “universal” CAR-T therapy. Thereby several issues could be overcome, such as the quality and quantity of patient cells for genetic modification and reduction of precious time for the patients between cell collection and administration of modified cells. Furthermore, manufacturing following an off-the-shelf rather than an individualized approach is suggested to reduce logistical complexity.

The challenge with allogeneic CAR-T cells is, however, how to best overcome major histocompatibility complex (MHC) barriers. In this regard, genome editing technologies offer promising strategies.

While CAR-T cells typically target surface tumor-associated antigens, engineered T cell receptors (TCRs) offer the exploitation of the intracellular tumor-associated antigen repertoire that is presented by the MHC. As the intracellular antigen repertoire accounts for approximately 70% of the human proteome compared with 30% for surface proteins, targeting tumors by engineered TCRs offers a significant potential.

Beyond cell-based approaches, research is ongoing to develop bispecific molecule formats harnessing the potential of TCRs to exploit the intracellular tumor-associated antigen repertoire and building on the power of bispecific T-cell engaging antibodies. A perfect example for how one area of research leads to another.

Figure 1: Harnessing the power of the immune system - From bispecific antibodies [4] to CAR-Ts [5] and TCRs [5] up to bispecific TCRs [6]

For further details please refer to our recently published Article “Approval of First CAR-Ts: Have we Solved all Hurdles for ATMPs?

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[1] Seimetz D, Lindhofer H, Bokemeyer C. Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) as a targeted cancer immunotherapy. Cancer Treat Rev. 2010;36(6):458–67. DOI: 10.1016/j.ctrv.2010.03.001.

[2] Le Jeune C, Thomas X. Potential for bispecific T-cell engagers: Role of blinatumomab in acute lymphoblastic leukemia. Drug Des Devel Ther. 2016;10:757–65. DOI: 10.2147/DDDT. S83848.

[3] FDA. Press Announcements - FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm581216.htm (2017, accessed 4 October 2018).

[4] Removab/catumaxomab product monograph, accessed on https://hemonc.org/docs/packageinsert/catumaxomab.pdf (access date 11 February 2019)

[5] Kite Pharma, presented during EMA workshop on CAR-Ts (November 2016)

[6] Immatics, product pipline, accessed on https://immatics.com/tcer.html (access date 11 February 2019)