CDX-1140, a Novel Agonist CD40 Antibody with Potent Anti-Lymphoma Activity

CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, is essential for activating both innate and adaptive immune systems. CD40 is expressed by antigen-presenting cells (APC) including dendritic cells and B cells. The engagement by its natural ligand (CD40L) on T cells activates APC thus enhancing immune responses. CD40 is also expressed on many cancer cells, in particular B cell lymphomas, and agonist CD40 antibodies can lead to apoptosis and impaired growth of cancer cells due to direct signaling effects. There are several CD40 agonist antibodies in clinical development, which are differentiated by their level of agonist activity, route of administration, and associated side effect profile. We have generated a panel of CD40-specific fully human antibodies derived from human immunoglobulin transgenic mice with the aim to select a clinical candidate with strong agonist activity and a safety profile that allows for systemic dosing. CDX-1140 is a human IgG2 antibody that stimulates CD40 signaling without the requirement for cross-linking or Fc receptor interactions. CDX-1140 is a potent stimulator of human B cells and dendritic cells in vitro, and has potent direct anti-tumor activity against B cell lymphoma cell lines transplanted into immunocompromised mice. To demonstrate the contribution of immune cell activation to the anti-lymphoma activity in vivo, we included human PBMCs in subsequent xenograft studies. Using human B cell lymphoma cell lines Raji and Ramos as tumor models and severe combined immunodeficiency mice (SCID-beige) as hosts, we found that addition of human PBMC alone had a minor impact on tumor growth (median survival 32 days, compared to 26 days with no treatment, p<0.01). Administration of CDX-1140 alone showed partial anti-tumor activity (median survival 39 days, p< 0.001), while the combination of human PBMCs and CDX-1140 provided a significant increase in survival with all mice alive at day 45. These studies provide evidence that CDX-1140 is able to induce in vivo activation and anti-tumor activity of effector cells derived from injected human PBMC, in addition to the direct signaling effects on lymphoma cells. We are investigating anti-lymphoma efficacy of combining CDX-1140 with other immunotherapies including varlilumab, our CD27 agonist antibody, which is currently in clinical development. Together with our prior preclinical studies characterizing this antibody, these results suggest that CDX-1140 is a promising candidate for clinical development in patients with lymphomas.