Background/Purpose: CD20-directed B-cell depletion therapy shows efficacy in hematological malignancies and in multiple autoimmune indications. More recently, promising data for the use of CD19-targeted B-cell depletion and in particular CD19 CAR-T cell therapies were reported for the treatment of autoimmune diseases. 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). Here we report key preclinical characteristics and the design of the ongoing Phase 1 study of RO7507062 in SLE patients.

Methods: 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 in humanized (using CD34+ cord blood cells) NSG mice and cynomolgus monkeys. A first in human study is ongoing in patients with SLE.

Results: 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 than i.v, leading to similarly efficient peripheral B-cell depletion (< 5 CD20+ B cells /ul blood) with less cytokine release. Fractionated dosing further increased the s.c tolerability. 

The first-in-human study with s.c. administration of RO7507062 (NCT05835986) has been initiated and consists of two parts: a 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 assessed.

Conclusion: 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-of-ro7507062-a-cd19-targeting-t-cell-bispecific-antibody-cd19tcb-and-design-of-its-ongoing-phase-1-trial-in-systemic-lupus-erythematosus/