DeFT
Deimmunization of Functional Therapeutics
Protect Your Therapeutic from Immune System Response
The FDA has suggested that protein therapeutics developers assess and manage unwanted immunogenicity. DeFT™ is cost effective and highly accurate in establishing and eliminating the immunogenic risks hidden within your protein therapeutic or biologic. Our deimmunization strategy is focused on the identification and elimination of T-cell epitopes contained within your candidate sequence.
DeFT™ (Deimmunization and functional tolerization) is a tested process of analysis, reengineering and confirmation. We provide critical immunogenic data about your protein therapeutic. In cases where functional sequences are also immunogenic, we identify key amino acid residues that are crucial to MHC binding. Minimal modification of a few non-functional amino acid residues may be all that is needed to protect your effective therapeutic from an immune response.
EpiVax’ approach to deimmunization is strategic epitope modification. Using a tool called OptiMatrix, EpiVax can reiteratively substitute amino acids in key HLA binding positions, identifying those that neither disturb the three-dimensional structure of the protein nor introduce novel epitopes. The EpiVax approach, termed DeFT (for Deimmunization of Functional Therapeutics) is a directed version of the process that occurs naturally when tumor cells [[i]] and pathogens [[ii],[iii]] evolve to escape immune pressure by accumulating mutations that reduce the binding of their constituent epitopes to host HLA [[iv]], rendering the host cell unable to “signal” to T cells the presence of the tumor or pathogen. The existence of these viable “immune escape mutants” demonstrates that proteins, and indeed whole organisms, can tolerate certain deimmunizing mutations.
Tregitope:
Tregitopes are a set of peptides that specifically activate CD4+CD25+FoxP3+ natural regulatory T cells (nTregs). Tregitopes are promiscuous MHC Class II T cell epitopes located in the Fc and framework regions of Fab from IgG. In vitro, co-incubation of antigens with Tregitopes in vitro leads to a suppression of effector cytokine and chemokine secretion, reduced proliferation of effector T cells, and expansion of antigen-specific adaptive Tregs (aTregs). In vivo, co-administration of Tregitopes with a wide range of proteins (such as FVIII, thyroid stimulating hormone receptor, ovalbumin, and autoantigens) leads to suppression of T cell and antibody responses to test antigens.
EpiVax is currently licensing Tregitope under 1 year option + license agreements. For more information on Tregitope and licensing opportunities please contact Jason Del Pozzo at bda@epivax.com.
[i]. Scanlan MJ, Jager D. Challenges to the development of antigen-specific breast cancer vaccines. Breast Cancer Res. 2001;3(2):95-8.
[ii]. Mullbacher A. Viral escape from immune recognition: multiple strategies of adenoviruses. Immunol Cell Biol. 1992 Feb;70 ( Pt 1):59-63. Hill et al 1997
[iii]. Hill AV, Jepson A, Plebanski M, Gilbert SC. Genetic analysis of host-parasite coevolution in human malaria. Philos Trans R Soc Lond B Biol Sci. 1997 Sep 29;352(1359):1317-25.
[iv]. Vossen MT, Westerhout EM, Soderberg-Naucler C, Wiertz EJ.Viral immune evasion: a masterpiece of evolution. Immunogenetics. 2002 Nov;54(8):527-42.2002 Oct 24.
