GPR183 mediates the capacity of the novel CD47-CD19 bispecific antibody TG-1801 to heighten ublituximab-umbralisib (U2) anti-lymphoma activity

Ribeiro, M.; Profitos-Peleja, N.; Santos, J. C.; Blecua, P.; Reyes Garau, D.; Armengol, M.; Fernandez-Serrano, M.; Miskin, H. P.; Bosch, F.; Esteller, M.; Normant, E.; Roue, G.

doi:10.1101/2022.03.31.486558

bioRxiv · 10.1101/2022.03.31.486558

GPR183 mediates the capacity of the novel CD47-CD19 bispecific antibody TG-1801 to heighten ublituximab-umbralisib (U2) anti-lymphoma activity

Ribeiro, M.·Profitos-Peleja, N.·Santos, J. C.·Blecua, P.·Reyes Garau, D.·Armengol, M.·Fernandez-Serrano, M.·Miskin, H. P.·Bosch, F.·Esteller, M.·Normant, E.·Roue, G.

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Abstract

Targeted therapies have considerably improved the survival rate of B-cell non-Hodgkin lymphoma (B-NHL) patients in the last decade; however, most subtypes remain incurable. TG-1801, a bispecific antibody that targets CD47 selectively on CD19+ B-cells, is under clinical evaluation in relapsed/refractory B-NHL patients either as a single-agent or in combination with ublituximab, a CD20 antibody, which is also being combined with the PI3K{delta}/CK1e inhibitor, umbralisib ("U2"-regimen). In this study, we demonstrated that TG-1801 potentiates ublituximab-mediated antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP), leading to an additive anti-tumour effect of the TG-1801/U2 combination in B-NHL co-cultures. Accordingly, in a B-NHL xenotransplant model, the triplet achieved a 93% tumour growth inhibition, with 40% of the animals remaining tumour-free 35 days after the last dosing. Transcriptomic analysis further uncovered the upregulation of the G protein-coupled receptor, GPR183, as a crucial event associated with TG-1801/U2 synergism, while pharmacological blockade or genetic depletion of this factor impaired ADCP initiation, as well as cytoskeleton remodelling and cell migration, in B-NHL cultures exposed to the drug combination. Thus, our results set the preclinical rationale and support a combination strategy of TG-1801 with PI3K{delta}- and CD20-targeting agents in patients with B-NHL.

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Ribeiro, M., Profitos-Peleja, N., Santos, J. C., Blecua, P., Reyes Garau, D., Armengol, M., Fernandez-Serrano, M., Miskin, H. P., Bosch, F., Esteller, M., Normant, E., Roue, G.. 2022-04-01. GPR183 mediates the capacity of the novel CD47-CD19 bispecific antibody TG-1801 to heighten ublituximab-umbralisib (U2) anti-lymphoma activity. https://doi.org/10.1101/2022.03.31.486558

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