Unlocking the Potential of CDX-1140: A New Era in Agonist CD40 Antibody for Lymphoma Treatment

CD40, a receptor in the TNFR family, is crucial for the activation of both innate and adaptive immunity. It is found on antigen-presenting cells such as dendritic and B cells, and its interaction with CD40L on T cells boosts immune responses. CD40 is also present on various cancer cells, notably B cell lymphomas, where agonist antibodies can trigger apoptosis and hinder cancer growth through direct signaling. Various CD40 agonist antibodies are in clinical trials, distinguished by their efficacy, administration method, and side effects.

A set of fully human antibodies targeting CD40 has been developed from transgenic mice with human immunoglobulins, with the goal of selecting a candidate with potent agonist properties and a safe profile for systemic administration. CDX-1140, a human IgG2 antibody, activates CD40 signaling without needing cross-linking or Fc receptor engagement. It is a strong activator of human B cells and dendritic cells in vitro and exhibits significant direct anti-tumor effects on B cell lymphoma lines in immunodeficient mice.

To assess the role of immune cell activation in anti-lymphoma activity, human PBMCs were included in xenograft studies. Using Raji and Ramos as B cell lymphoma models and SCID-beige mice, the addition of human PBMCs slightly affected tumor growth, extending median survival from 26 to 32 days. CDX-1140 alone showed some anti-tumor activity, increasing median survival to 39 days. However, combining human PBMCs with CDX-1140 significantly improved survival, with all mice alive at day 45.

These findings indicate that CDX-1140 can stimulate in vivo activation and anti-tumor effects of human PBMC-derived effector cells, as well as exert direct effects on lymphoma cells. Studies are underway to evaluate the anti-lymphoma efficacy of combining CDX-1140 with other immunotherapies, such as varlilumab, a CD27 agonist antibody in development. The results, along with previous preclinical studies, indicate that CDX-1140 is a promising candidate for clinical trials in lymphoma patients.

The disclosures section lists several individuals employed by Celldex Therapeutics, Inc., and one with both employment and equity ownership.