RG7827

In this work, a workflow to select binding affinities for bispecific antibodies that integrates preclinical in vitro data, mathematical modeling and simulation, and knowledge on target expression in the patient population, is provided. The early implementation of this approach can increase the probability of success with cancer immunotherapy in clinical development.

P1/2, N=645, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | Trial completion date: Nov 2027 --> May 2026

P1/2, N=80, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Jul 2025 --> Dec 2024 | Trial primary completion date: Jul 2025 --> Dec 2024

P1/2, N=80, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

We integrated in vitro data with mathematical modeling to characterize the pharmacology of FAP-4-1BBL as a function of trimeric complex formation when combined with the T-cell engager cibisatamab. Depending on the dosing schedule and FAP-4-1BBL plasma: tumor distribution, doses between 2 and 145 mg could lead to maximum trimeric complex formation in the clinic. Due to the expected variability in both pharmacokinetic and FAP expression in the patient population, we predict that detecting a clear dose-response relationship would remain difficult without a large number of patients per dose level, highlighting that mathematical modeling techniques based on in vitro data could aid dose selection.

Findings from a phase I study of the bispecific antibody RO7122290, which targets CD137 and the fibroblast activity protein, show that it produces responses in patients with advanced solid tumors-without the liver toxicity associated with earlier therapies targeting CD137. Additional research evaluating RO7122290 in combination with atezolizumab or other immune agents is planned.

Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.

Robust immune memory was observed in re-challenge experiments.Conclusion. Our data provides a proof-of-concept and mechanistic insights pertaining the therapeutic efficacy of the bispecific FAP-41BBL fusion protein combined with local radiotherapy.

P1/2, N=80, Recruiting, Hoffmann-La Roche | Trial completion date: Oct 2024 --> Jul 2025 | Trial primary completion date: Oct 2024 --> Jul 2025

P1/2, N=645, Recruiting, Hoffmann-La Roche | Trial completion date: Jun 2026 --> Aug 2027 | Trial primary completion date: Jul 2023 --> Nov 2024

Moreover, lymphoma-FRCs upregulated expression of inhibitory PD-1 ligands that reduced the anti-tumor cytolytic activity of CD8+ T cells, a T cell bispecific antibody (CD20-TCB, glofitamab) and anti-CD19 CAR T cells in our coculture models.To overcome the immunosuppressive activity of DLBCL-FRCs, we investigated the use of CD20-TCB in combination with stroma-targeting immunocytokine fusion protein drug (FAP-IL2v, RG7461) or costimulatory fusion protein (FAP-4-1BBL, RG7827). In addition, the ability of immune- /stroma- targeted combination immunotherapy to trigger anti-tumor activity and CD8+ T cell retention within the FRC-TME was demonstrated using 3D precision-cut lymph node slice-based organotypic cultures of DLBCL and other B cell malignancies.In conclusion our data reveal that lymphoma cells actively reprogram FRCs that acquire altered immunoregulatory function which prevents effective T cell motility and suppresses the anti-tumor function of cytolytic T cells. Importantly, we demonstrate that combination immunotherapy incorporating fibroblast-targeting fusion proteins could effectively recover anti-tumor T cell activity.