AB1034 CHARACTERIZATION OF RO7507062, A CD19-TARGETING T-CELL BISPECIFIC ANTIBODY (CD19TCB), AND DESIGN OF A PHASE 1 TRIAL IN SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: F. Kollert, F. Regenass, R. Hallet, J. Neale, C. M. Looney, N. Frances, C. Marban-Doran, S. F. Soehrman, L. Millar, R. Finch, H. Ji, A. Frei, J. Sam, B. Fisher, T. Dörner, C. Klein, F. Schuler
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Despite the success of B-cell depletion therapy in multiple autoimmune indications, efficacy is limited likely due to incomplete depletion of CD19+ tissue resident B cells. Recently, promising data for the use of CD19 CAR-T cell therapies for the treatment of autoimmune diseases were reported. T-cell engaging bispecific antibodies (TCB) lead to profound anti-tumor activity and have been approved for the treatment of relapsed or refractory B cell lymphoma patients, yet cytokine release is a dose-limiting side effect. We have developed a novel CD19-targeting TCB, RO7507062, optimized to mediate profound B cell depletion with low systemic cytokine release. RO7507062 may become a potential off-the-shelf treatment for patients with systemic lupus erythematosus (SLE) and other autoimmune diseases, and is being evaluated in a Phase 1 study (NCT05835986). <h3>Objectives:</h3> Profiling of key preclinical characteristics and design of the Phase 1 study of RO7507062 in SLE patients. <h3>Methods:</h3> In vitro B cell depletion by RO7507062 was evaluated in human peripheral blood mononuclear cells (PBMCs). The in vivo B-cell depletion efficacy and cytokine release profile of RO7507062 were assessed using humanized (using CD34+ cord blood cells) NSG mice and cynomolgus monkeys. A first in human study was designed in patients with SLE. <h3>Results:</h3> RO7507062 led to a concentration-dependent depletion of B cells in human PBMCs in vitro. In humanized NSG mice, a single intravenous (i.v.) injection of RO7507062 led to potent and deep depletion of B cells in peripheral blood, lymph nodes, spleen and bone marrow. Blood cytokine levels were only modestly increased and did not lead to notable clinical signs. In cynomolgus monkeys, i.v. injection of RO7507062 led to dose-dependent B cell depletion, cytokine release and mild, transient clinical signs of cytokine release syndrome (CRS) at the highest dose. Cytokine release peaked at 2-6 hours after administration and returned to baseline within 72 hours post administration. Subcutaneous administration (s.c.) of RO7507062 to cynomolgus monkeys was better tolerated with less cytokine release and led to similarly efficient peripheral B cell depletion (&lt; 5 CD20+ B cells/ul blood) as with i.v. administration. Fractionated dosing further increased the tolerability. The first-in-human study with s.c. administration of RO7507062 (NCT05835986) has been initiated and consists of two parts: single ascending dose (Part 1) and dose escalation with fractionated dosing (Part 2). In Part 2, two administrations will be given seven days apart, with the first dose defined based on Part 1 data and the second dose escalated. Key endpoints of NCT05835986 are safety, tolerability, and pharmacokinetics. Pharmacodynamics of RO7507062, including T cell activation, cytokine release and B cell depletion, will also be explored. <h3>Conclusion:</h3> RO7507062 was designed as a next generation off-the-shelf B-cell depleter dedicated for patients with autoimmune diseases. A first-in-human study in patients with SLE is ongoing. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> Florian Kollert Shareholder of Roche, Currently employed by Roche, Franziska Regenass Shareholer of Roche, Currently employed by Roche, Remy Hallet Shareholder of Roche, Currently employed by Roche, Jason Neale Shareholder of Roche, Currently employed by Roche, Cary M. Looney Roche shareholder, Currently employed by Roche, Nicolas Frances Shareholder of Roche, Currently employed by Roche, Celine Marban-Doran Shareholder of Roche, Currently employed by Roche, Sophia Frederika Soehrman Shareholder of Roche, Currently employed by Roche, Laurie Millar Shareholder of Roche, Currently employed by Roche, Rebecca Finch Shareholder of Roche, Currently employed by Roche, Hong Ji Shareholder of Roche, Currently employed by Roche, Andreas Frei Shareholder of Roche, Currently employed by Roche, Johannes Sam Shareholder of Roche, Currently employed by Roche, Benjamin Fisher Consultancy to Novartis, BMS, Servier, Galapagos, UCB, Sanofi, Janssen, Roche , Funding: Janssen, Servier, Galapagos, Celgene, Thomas Dörner Novartis, Janssen, Eli Lilly, GSK, Roche, Novartis, Janssen, Eli Lilly, GSK, Roche, Christian Klein Shareholder of Roche, Currently employed by Roche, Franz Schuler Shareholder of Roche, Currently employed by Roche.