Scientific Associate Director Amgen, United States
Disclosure(s):
Fiona Chandra: No financial relationships to disclose
Objectives: CD19-targeting therapies have garnered attention as promising treatments for inflammatory autoimmune diseases as autoreactive B cells are key drivers of autoimmune diseases. For certain inflammatory autoimmune diseases, it is thought that disease severity is associated with B cell levels in certain tissues rather than in the blood. Therefore, a mechanistic PK/PD model was developed to guide dose selection for subcutaneous blinatumomab, a CD19-targeting bispecific T cell engager, in patients with inflammatory autoimmune diseases.
Results: The PK/PD model describes the biodistribution of drug from serum to target tissues of synovial fluid and lymph nodes using a minimal physiologically based PK (PBPK) model. Within each tissue compartment, the drug binding to B and T cells was modeled1. The resulting trimer drives depletion of target cells (B cells). Rates of B cell depletion were estimated using unpublished data of B cell dynamics in blood following blinatumomab treatment in subjects with acute lymphoblastic leukemia. B cell repletion rate was estimated using published B cell data in a subject with systemic sclerosis after blinatumomab treatment2. These rates were assumed to be the same across tissues.
Results: B cell depletion in target tissues was then simulated as an efficacy marker for patients with inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE). The model allows for dose selection of subcutaneous administration of blinatumomab in subjects with autoimmune disease by simulating the dosing regimens that achieve ≥90% depletion of B cells in target tissues (lymph nodes in rheumatoid arthritis and synovial fluid in SLE).
Conclusions: A mechanistic PKPD model was developed to simulate B cell depletion in tissues in order to guide dose selection for subcutaneous blinatumomab in patients with inflammatory autoimmune disease. The model can also be adapted to guide efficacious dose determination for other CD19-targeting therapies.
Citations: [1] Jiang X, Chen X, Jaiprasart P, et al. Eur J of Pharm Sci 146 (2020): 105260 [2] Subklewe M, Magno G, Gebhardt C, et al. Eur J of Cancer 204 (2024): 114071
