Protecting immune system by modulators of p53 and NF-kB

Gudkov, Andrei

Abstract

This proposal deals with a new class of radioprotectors - natural products generated by microbes and tumor cells that act by activating internal cellular mechanisms of defense and inhibiting programmed cell death (apoptosis) as part of natural survival strategy in the host organism. Specifically, it is focused on development of the product originating from flagellin of Salmonella and latent form of human TGFbeta2, both acting as NF-kappaB-activating agents through interaction with specific cellular receptors (toll-like receptor 5 and TGFbeta receptors 1 and 2, respectively). During our preliminary work, we have completed structure-functional optimization of both factors and created products named, which demonstrated powerful anti-apoptotic activity. CBLB502 has been thoroughly characterized in vivo and showed outstanding efficacy against hematopoietic and gastro-intestinal radiation syndromes, thus validating our approach to radioprotection. So far we have been working with lethal radiation doses and treatment of acute consequences of radiation injury. The success of this program allows us now to address another radioprotective aspect of activity of our products - protection of the immune system - and to evaluate the perspectives of their use for this indication. The study involves: (i) thorough characterization of protective effect of both products on different compartments of immune system (adaptive, innate immunity and stromal components), (ii) evaluation of safety of CBLB502 and CBLB102 by estimation of their effect on radiation-induced carcinogenesis and (iii) testing their protective effect in non-human primates as an essential and final step before full-scale program of development of at least one of the tested compounds into radioprotecting drug.