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Figure 6: CD40L/CD40-based agonists for cancer therapy. Soluble CD40L is only capable of sub-optimal CD40 signaling. However, enforced trimerization of CD40L or agonistic antiCD40 antibodies can trigger effective CD40-signaling, but with severe side-effects due to ubiquitous CD40-activation. Of note, CD40 agonist antibodies require FcR-mediated cross-linking for effective CD40-signaling. In an antibody fragment-targeted scFv:CD40L fusion protein, the CD40L domain is relatively inactive en route, but gains membrane-like activity upon target antigen-mediated binding. Further, CD40L can be virally transduced into tumor cells, using AdCD40L, to optimize CD40-mediated co-stimulation.