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- Figure 1 Phase I Clinical Trial Design
Initial cohort received anti-CD40L mAb 1 mg/kg IV; dose was escalated in each successive cohort: 5, 10, and 15 mg/kg. The primary outcome was safety. The secondary outcome was pharmacokinetics. Exploratory measures included immunologic analysis, clinical assessment of relapse and EDSS score, neuropsychological test, and MRI. mAb = monoclonal antibody.
- Figure 2 Leukocyte and Lymphocyte Changes After Anti-CD40L
(A) Percentage changes of total CD3+, CD3+CD4+, and CD3+CD8+ over time for each patient according to dose tier. (B) Leukocyte and lymphocyte count for all patients.
- Figure 3 Heat Maps of CD25 and Anti-inflammatory Cytokine Shift After Anti-CD40L
(A) Increased CD25/CD3 and CD25/CD4 ratios were seen following treatment. Flow cytometry measured CD25+ vs CD3+ and CD4+ shift after treatment as Z-score heat map. The values on the heat map indicate the ratio of CD25+ cells compared with CD3+ (left) and CD4+ (right). The heat map indicates the change over time in individual patients in the high-dose group (15 mg/kg). (B) IL10/MCP1 and IL10/IL17 were increased following treatment in the same patients. Cytokines in PBMC culture supernatant were measured. Quantity of anti-inflammatory IL10 and proinflammatory cytokine MCP1 and IL17 was measured, and their ratios are presented as Z-score heat map. The ratios are derived by dividing the concentration of IL10 by the concentration of MCP1 (left) or the concentration of IL10 by the concentration of IL17 (right). Across all patients and time points, IL10 ranged between 197 and 565 pg/mL, MCP1 ranged between 5,280 and 15,627 pg/mL, and IL17 ranged between 54 and 1,138 pg/mL. The heat maps indicate the mean change over time in the high-dose group (15 mg/kg). MCP1 = monocyte chemoattractant protein-1; PBMC = peripheral blood mononuclear cell.
- Figure 4 Potential Mechanism of Action of Anti-CD40L mAb in Treating MS
Activation of T cells by B cell/antigen-presenting cells (APC) is dependent on engagement of costimulatory molecules and the successful activation of T cell receptor (TCR) signal. TCR signal is upregulated when the major histocompatibility complex class II (MHCII) containing the appropriate peptide on the B cell/APC is recognized by the TCR. This interaction leads to the upregulation of CD40L (CD154) on the T cell that engages the constitutively expressed CD40 on the APC. Monoclonal antibodies against CD40L (anti-CD40L mAb) block further activation of downstream signaling and prevent T- and B-cell activation; which can potentially induce tolerance in antigen-specific manner. mAb = monoclonal antibody; TCR = T-cell receptor.
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