Deimmunized Sarcin Ribotoxin
α-Sarcin is a small (17 kDa) fungal ribonuclease produced by Aspergillus giganteus. α-Sarcin functions by catalytically cleaving a single phosphodiester bond in the sarcin-ricin loop, a well-defined motif within the rRNA scaffold of the large ribosomal subunit. This cleavage makes the ribosome unrecognizable to elongation factors and hence, blocks protein synthesis inducing apoptosis (programmed cell death).
α-Sarcin has shown activity across various tumor cells lines and in animal models as a stand-alone protein and as a fusion protein with various tumor targeting molecules like antibodies and antibody fragments. RCT has developed a fully deimmunized version of a-Sarcin (“Sarcin-DI”) that will not activate T cells when administered to humans, thus, avoiding the potential safety issues as reported for other similar toxins like ricin and diphtheria toxin. Sarcin-DI should provide a large therapeutic window and a high objective response rate in humans with cancer when targeted with antibodies, antibody fragments or other protein scaffolds. RCT will work with partners in both academia and industry to develop the next generation of immunotoxins.
Immunotoxins are chimeric molecules containing a targeting moiety linked to a toxin and are primarily used as therapeutics to specifically target cells for destruction by the toxin and avoid normal healthy cells. The targeting portion is typically an antibody, antibody fragment, or some other targeting protein (e.g. cytokine, peptide, ligand, or hormone) designed to target a cell-surface molecule or receptor. OntakTM is a fusion protein containing the IL-2 cytokine plus a truncated form of diphtheria toxin and was the first, and only, immunotoxin approved by the FDA for the treatment of certain B cell leukemias.
Many toxin warheads have been tried as part of an immunotoxin therapeutic including: ricin, diphtheria toxin, pseudomonas exotoxin A, gelonin, and various mutants of each. Unfortunately, these toxins have been plagued as therapeutics for various reasons. First, many patients have pre-existing neutralizing antibodies to the toxin, or they quickly develop neutralizing antibodies to the toxin after one or two administrations. This immune response is due to the immunogenicity of the toxin. Second, many of these toxin proteins are difficult to produce in current expression systems due to low yields and toxicity of the toxin to the recombinant expression system. To address unwanted immunogenicity, one can identify and mutate the T cell epitopes within the toxin, thereby deimmunizing the toxin. However, for many toxins, mutating the T cell epitopes leads to inactivation of the toxin. To address manufacturing issues surrounding toxins, attempts have been made to truncate or mutate the toxin, or to modify the expression systems so they become resistant to the toxin.
RCT has deimmunized α-Sarcin to address the immunogenicity issues highlighted above. Additionally, RCT has demonstrated that Sarcin-DI is readily manufactured using a number of protein expression systems, including Pichia and E. coli. Parties interested in testing Sarcin-DI should contact RCT to receive material through our licensing program.