INDUSTRIAL RESEARCH ON THE BEAMLINES INDUSTRIAL RESEARCH

162 ESRF

Due to its proprietary nature, much of the commercial research carried out by industry at the ESRF cannot be disclosed. However, sometimes companies authorise the ESRF to discuss their work and they may even publish results or access the ESRF via the public programme whereby there is obligation to publish results. Below are a few examples from 2020.

Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co- stimulation, L. Wu (a), E. Seung (a), L. Xu (a), E. Rao (b), D.M. Lord (a), R.R. Wei (a), V. Cortez-Retamozo (a), B. Ospina (a), V. Posternak (a), G. Ulinski (a), P. Piepenhagen (a), E. Francesconi (c),

N. El-Murr (c), C. Beil (b), P. Kirby (a), A. Li (a), J. Fretland (a), R. Vicente (c), G. Deng (a), T. Dabdoubi (c), B. Cameron (c), T. Bertrand (c), P. Ferrari (c), S. Pouzieux (c), C. Lemoine (c), C. Prades (c), A. Park (a), H. Qiu (a), Z. Song (a), B. Zhang (a), F. Sun (a), M. Chiron (c), S. Rao (a), K. Radošević (c), Z. Yang (a) and G.J. Nabel (a),

Nat. Cancer 1, 86-98 (2020); https://doi. org/10.1038/s43018-019-0004-z. (a) Sanofi Research and Development, Sanofi North America, Cambridge (USA) (b) Sanofi Research and Development, Sanofi Frankfurt, Frankfurt (Germany) (c) Sanofi Research and Development, Sanofi Vitry, Paris (France)

PRINCIPAL PUBLICATION AND AUTHORS

OPTIMISING IMMUNOTHERAPY THROUGH THE DEVELOPMENT OF TRI-SPECIFIC ANTIBODIES One approach to improve the efficacy of immunotherapy in human cancer is to stimulate T cells while they are directed to malignant cell targets. A new tri-specific antibody that enhances T cell activation and tumour targeting shows improved protection against tumour growth.

Advances in the immunotherapy of human cancer have led to remarkable new therapies that reverse or contain the spread of malignant disease. Bi-specific antibodies targeting tumour antigens and activating T cell receptor signalling have shown clinical efficacy; however, providing co-stimulatory signals may improve T cell responses against tumours.

A tri-specific antibody that interacts with receptors CD38, CD3, and CD28, in order to enhance both T cell activation and tumour targeting, was developed. The engagement of both CD3 and CD28 affords efficient T cell

stimulation, whereas the anti-CD38 domain directs T cells to myeloma cells, as well as to certain lymphomas and leukaemias. A structural model for the tri-specific antibody (Figure 140) was constructed partly from X-ray diffraction data taken at beamline ID30B (CD28:CODV-Fab complex).

The antibody was shown to suppress myeloma growth, stimulate memory/effector T cell proliferation and reduce regulatory T cells, at well-tolerated doses. Collectively, tri-specific antibodies represent a promising platform for cancer immunotherapy.

Fig. 140: a) Configuration of the trispecific antibody. b) Model of the

crystal structures of anti-CD28sup x CD3mid CODV-Fab and the anti-

CD38VH1 Fab model.