Agonistic CD40 Antibodies in Cancer Treatment

Abstract

CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation (licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The Cancer Genome Atlas in melanoma, renal cell carcinoma, and pancreatic adenocarcinoma and found correlations between CD40 and several genes involved in antigen presentation and T cell function, supporting further exploration of CD40 agonists to treat cancer. Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other treatments (immune checkpoint inhibition, chemotherapy, and colony-stimulating factor 1 receptor inhibition). The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.

The Role of Tumor-Associated Macrophages in Hematologic Malignancies

“…The innate immune system defends the host from infections and non-self antigens in a non-specific manner; thus, it could be involved in the identification and destruction of neoplastic cells [ 1 , 2 , 3 ]. It includes natural physical barriers, the complement system, natural killer (NK) cells, mast cells, dendritic cells, neutrophils, eosinophils, basophils, monocytes and macrophages.…”

Injectable Nanoparticle-Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies

“…Immunostimulatory drugs such as CD40 agonists, cytokines, TLR agonists, and bispecific antibodies provide a means for repolarizing the immunosuppressive tumor microenvironment toward an immunogenic state. Preclinical and clinical data indicate that incorporating these drugs into combination immunotherapy regimens can significantly improve outcomes for a variety of tumors that fail to respond to either traditional or singleagent immunotherapies (13,25,59,60). Yet, clinical translation of immunostimulatory drugs has been greatly hindered by their propensity toward triggering dose-limiting IRAEs (61).…”

Immunogenic Cell Death Induction by Ionizing Radiation

“…CD91 also combines with HSP90 to facilitate cross-presentation ( 21 ). CD40 is a costimulatory molecule belonging to the TNF receptor superfamily and mainly expressed on APCs ( 22 ). HSP70 binding to CD40 results in CD8 + cytotoxic T-cell activation ( 6 ).…”