Next Generation CD40 Agonistic Antibodies for Cancer Immunotherapy

Abstract

The clinical use of anti-CD40 agonist monoclonal antibodies (mAbs) is aimed at recruiting the immune system to fight the tumor cells. This approach has been demonstrated to be effective in various preclinical models. However, human CD40 Abs displayed only modest antitumor activity in cancer patients, characterized by low efficacy and dose-limiting toxicity. While recent studies highlight the importance of engineering the Fc region of human CD40 mAbs to optimize their agonistic potency, toxicity remains the main limiting factor, restricting clinical application to suboptimal doses. Here, we discuss the current challenges in realizing the full potential of CD40 mAbs in clinical practice, and describe novel approaches designed to circumvent the systemic toxicity associated with CD40 agonism.

Treg-selective IL-2 starvation synergizes with CD40 activation to sustain durable responses in lymphoma models

“…CD40-directed agonistic antibodies were not initially developed to directly target, and kill, CD40-expressing tumor cells but rather to increase the number and quality of tumor-infiltrating T-cells and thereby, response effectiveness, in CD40-negative solid organ malignancies. [50][51][52] In such settings of CD40-negative malignancies, CD40 on antigen-presenting cells (APCs) plays a central role in stimulating immune synapses, including during T-cell priming, when its interaction with the CD40 ligand (CD40L) licenses DCs to activate antigen-specific T-cells. 53 The situation is complicated in B-cell malignancies by varying extents of tumor-intrinsic CD40 expression; chronic lymphocytic leukaemia, Burkitt lymphoma and DLBCL cells have all been reported to express CD40 and to respond to CD40 activation with activationinduced cell death (AICD) in vitro and/or in experimental models.…”

Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity

“…Such approaches have been expedited by the innovative design of bispecific antibodies targeting tumor-associated antigens or dendritic cell surface markers, in addition to CD40, or by selective delivery of CD40 agonists into the tumor tissue. [42][43][44][45][46][47][48] The practical translation of our RBC-based macrophage reprogramming approach has to be defined in future preclinical studies focused on tolerability, safety, and efficacy. A significant parameter to be defined is how to reach a level of erythrophagocytosis in the liver sufficient to achieve consistent liver protection while avoiding severe hemolytic anemia.…”

Recent Advances in Cancer Immunotherapy Delivery Modalities

“…Agonistic antibodies are specifically designed to bind to T cell receptors and activate intracellular signaling pathways in order to effectively combat cancer cells. Monoclonal antibodies (mAbs) targeting immune checkpoints such as CTLA-4 and PD1/PD-L1 have recently been developed for antitumor activity [ 45 ]. Agonist mAbs developed against the CD40 immune receptor can increase the tumor-infiltrating T cells (TILs), which can effectively eliminate cancer cells [ 46 ].When CD40 interacts with CD40 ligand in dendritic cells, it activates specific T cells, triggering a cascade of antitumor responses [ 47 ].…”