SUN-876 - Preclinical Pharmacokinetic and Pharmacodynamic Profile of Lu AG22515, a CD40-Ligand Blocker in Development for Thyroid Eye Disease

Background: Lu AG22515 is a recombinant (scFv)2-Fab fusion protein that binds to the therapeutic target CD40 ligand (CD40L) and human serum albumin (HSA) to extend half-life. Lu AG22515 blocks the binding of CD40L to CD40, a pathway that has been implicated in the pathogenesis of several autoimmune diseases.

Objective: To evaluate the inhibitory effect and the pharmacokinetic/pharmacodynamic (PK/PD) profile of Lu AG22515 in preclinical models.

Methods: Biochemical function of Lu AG22515 was assessed via inhibition assays against membrane-bound and soluble CD40L (sCD40L). Inhibition of B-cell proliferation was assessed in human peripheral blood mononuclear cells stimulated with interleukin (IL)-21 (positive control), anti-immunoglobulin (Ig) M (negative control), and CD40L. Proinflammatory cytokine production was assessed in interferon-γ-stimulated human primary fibroblasts. Preclinical PK/PD assessments were conducted in cynomolgus monkeys, using the Keyhole Limpet Hemocyanin (KLH) T-dependent antibody response (TDAR) assay.

Results: In vitro evaluation of Lu AG22515 showed a concentration-dependent inhibitory effect towards both membrane-bound CD40L and sCD40L: half maximal inhibition concentration values were 0.299 nM and 0.637 nM, respectively. HSA binding did not affect the binding and inhibitory activity of Lu AG22515. Lu AG22515 blocked the activation and differentiation of human B cells to plasma cells in a dose-dependent manner. A dose-dependent inhibition of CD40L-induced cytokine (IL-6, IL-8, and C-C motif chemokine 5) production was observed in human primary fibroblasts treated with Lu AG22515, with full inhibition at the highest CD40L blocker concentrations tested (Emax=100%; potency range between 30 and 150 nM).
Lu AG22515 displayed a linear PK profile in a multiple-dose study in cynomolgus monkeys. The elimination half-life ranged from 6.9 to 10.1 days. Lu AG22515 dose-dependently suppressed TDAR after immunization with KLH; specifically, the 10 and 30 mg/kg doses significantly decreased the anti-KLH IgG antibody titer. This was associated with a decrease in cellularity of the germinal center in draining lymph nodes and with a reduction of dividing B cells.

Conclusion: These data demonstrate that Lu AG22515, an immunomodulator that blocks CD40L, is a promising candidate with potent inhibitory activity and a PK/PD profile that supports its continued clinical development. A phase 1b trial (NCT06557850) evaluating Lu AG22515 in adults with moderate-to-severe thyroid eye disease is ongoing.