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Engineering Antigens for in Situ Erythrocyte Binding Induces T-Cell Deletion

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Engineering Antigens for in Situ Erythrocyte Binding Induces T-Cell Deletion Engineering antigens for in situ erythrocyte binding induces T-cell deletion Stephan Kontosa,1, Iraklis C. Kourtisa, Karen Y. Danea, and Jeffrey A. Hubbella,b,c,2 aInstitute of Bioengineering, School of Life Sciences and School of Engineering, and bInstitute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale Lausanne, CH-1015 Lausanne, Switzerland; and cDiabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136 Edited by George Georgiou, University of Texas at Austin, Austin, TX, and accepted by the Editorial Board November 17, 2012 (received for review September 26, 2012) Antigens derived from apoptotic cell debris can drive clonal T-cell autoimmunity in type 1 diabetes (8) and myocarditis (9), trans- deletion or anergy, and antigens chemically coupled ex vivo to plant tolerance (10), and allergy (11). Antigen has also been loaded apoptotic cell surfaces have been shown correspondingly to induce osmotically into splenocytes, with the osmotic shock inducing tolerance on infusion. Reasoning that a large number of erythro- apoptosis, in the context of tolerance to the model antigen ov- cytes become apoptotic (eryptotic) and are cleared each day, we albumin (OVA) (12). Although results obtained with these cel- engineered two different antigen constructs to target the antigen to lular approaches have been remarkable, the complexities of erythrocyte cell surfaces after i.v. injection, one using a conjugate translating such a cellular therapeutic approach to widespread with an erythrocyte-binding peptide and another using a fusion clinical use are formidable; despite these challenges, a phase I/ with an antibody fragment, both targeting the erythrocyte-specific IIA trial has been carried out with peripheral blood mononuclear cell surface marker glycophorin A. Here, we show that erythrocyte- cells pulsed with multiple peptide epitopes in the context of re- binding antigen is collected much more efficiently than free antigen lapsing-remitting multiple sclerosis (European Union Drug by splenic and hepatic immune cell populations and hepatocytes, Regulating Authorities Clinical Trials no. 2008-004408-29). For + and that it induces antigen-specific deletional responses in CD4 and ease of translation to widespread clinical use, an acellular tol- + CD8 T cells. We further validated T-cell deletion driven by erythro- erogenic therapeutic approach composed only of simpler defined + cyte-binding antigens using a transgenic islet β cell-reactive CD4 biomolecules would be advantageous. For this, we turned to T-cell adoptive transfer model of autoimmune type 1 diabetes: engineering the antigen to enable in situ cell surface binding after Treatment with the peptide antigen fused to an erythrocyte-binding simple i.v. injection. antibody fragment completely prevented diabetes onset induced by We reasoned that the large number of erythrocytes cleared + the activated, autoreactive CD4 T cells. Thus, we report a translat- after apoptosis-like programmed cell death (eryptosis) each day able modular biomolecular approach with which to engineer anti- (more than 1% per day in humans and 4% in mice) (13) could gens for targeted binding to erythrocyte cell surfaces to induce be exploited to induce antigen-specific T-cell deletion. Although fi + + antigen-speci c CD4 and CD8 T-cell deletion toward exogenous the exact triggers of erythrocyte clearance remain unclear, eryp- antigens and autoantigens. totic erythrocytes are characterized by phosphatidylserine asym- metry, membrane heterogeneity, and annexin-V binding, analogous autoimmunity | immune tolerance | BDC2.5 | TER119 | to apoptotic nucleated cells (13, 14). Rather than chemically con- immunoengineering jugate erythrocytes to an antigen ex vivo, as has been mentioned (15), we sought to develop a targeted antigen formulation that trategies to induce antigen-specific tolerance without the need would spontaneously bind strongly and specifically to erythrocytes Sfor systemic immunosuppression have great potential in pre- after simple i.v. injection for eventual display to APCs, along with venting immune responses in protein replacement therapies, graft- apoptotic markers, as the eryptotic erythrocyte fraction is cleared versus-host disease (GvHD), and autoimmune disorders (1). For over the ensuing days. example, in the treatment of diseases requiring replacement pro- tein administration, such as hemophilia, some patients mount Results immune responses to the therapeutic protein antigen, rendering Creation and Characterization of Erythrocyte-Binding OVA. As one treatment ineffective and dangerous (2). In autoimmune diseases, approach to obtain strong and specific biophysical targeting of an where peripheral tolerance mechanisms fail to inactivate autor- antigen to erythrocyte cell surfaces in situ, we used a synthetic eactive T cells that have escaped central tolerance induction in the 12-aa peptide (ERY1) that we discovered by phage display to thymus, deletion or functional inactivation to clonal anergy is con- bind to mouse glycophorin-A specifically (16), which is present sidered key to nonprogression of the disease (3). Immunoregulatory uniquely on erythrocytes. We used the model antigen OVA, so modalities capable of prophylactically educating or therapeutically reeducating the immune system to induce antigen-specifictolerance are greatly needed for these and many other situations. Author contributions: S.K., K.Y.D., and J.A.H. designed research; S.K., I.C.K., and K.Y.D. Apoptotic cells are well known as a source of tolerogenic anti- performed research; S.K. and I.C.K. analyzed data; and S.K. and J.A.H. wrote the paper. gens, although the exact mechanisms are not fully understood (4, Conflict of interest statement: The Ecole Polytechnique Fédérale Lausanne has filed for 5). Literature evidence maintains that antigen displayed in a phys- patent protection on the technology described here, and S.K., K.Y.D., and J.A.H. are iological noninflammatory manner by apoptotic cells to antigen- named as inventors on those patents; J.A.H. is a shareholder in a company that has presenting cells (APCs) fails to induce a productive immune re- licensed those patents. sponse, because Toll-like receptor signaling is inhibited by uptake This article is a PNAS Direct Submission. G.G. is a guest editor invited by the of apoptotic cellular debris (6), leading to antigen-specific T-cell Editorial Board. deletion or anergy (7). Freely available online through the PNAS open access option. The concept of engineering apoptotic cell carriers to induce 1Present address: Anokion SA, CH-1015 Lausanne, Switzerland. immunological tolerance has been explored. Notably, antigens 2To whom correspondence should be addressed. E-mail: jeffrey.hubbell@epfl.ch. chemically coupled ex vivo to splenocyte cell surfaces in a manner See Author Summary on page 17 (volume 110, number 1). so as to induce apoptosis in the splenocytes has been shown to This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. induce antigen-specific tolerance on infusion in such contexts as 1073/pnas.1216353110/-/DCSupplemental. E60–E68 | PNAS | Published online December 17, 2012 www.pnas.org/cgi/doi/10.1073/pnas.1216353110 Downloaded by guest on September 27, 2021 as to enable initial analysis in a transgenic mouse strain (OTI), A CD45+ CD45- PNAS PLUS the CD8+ T-cell population of which expresses the T-cell re- ceptor specific for the MHC I immunodominant OVA epitope, SIINFEKL. We chemically conjugated approximately three cop- ies of the ERY1 peptide to OVA to create an OVA variant (ERY1-OVA) that binds mouse erythrocytes with high affinity and specificity (Fig. 1A). High-resolution confocal microscopy naive naive showed localization to the cell membrane equatorial periphery B fl (Fig. 1 ), and ow cytometric analysis demonstrated binding to be OVA OVA sequence-specific (Fig. 1C). ERY1-OVA bound to erythrocytes with high affinity, exhibiting a dissociation constant (K ) of 6.2 ± d ERY1-OVA 1.3 nM, as determined by equilibrium binding measurements (Fig. ERY1-OVA 1D). Based on this approximate value, an entire 10 μg dose of 0101 102 103 0101 102 103 ERY1-OVA would be bound to the surface of erythrocytes fol- OVA binding lowing i.v. injection in a mouse. We validated ERY1-OVA binding in vivo to circulating eryth- B OVA ERY1-OVA rocytes following i.v. administration in mice. Whole-blood samples 0.11 3.75e-3 1.96e-3 0.25 taken 30 min following injection of 150 μg of either OVA or ERY1- 3 OVA confirmed the specific erythrocyte binding capability of 10 ERY1-OVA even amid the complex heterogeneous milieu of blood and the vasculature (Fig. 2A). Consistent with glycophorin- 102 − A association, ERY1-OVA bound to erythrocytes (CD45 ) but + not to leukocytes (CD45 ). ERY1-OVA binding was unbiased as 101 to the eryptotic state of the erythrocytes, binding strongly to + − − B both annexin-V and annexin-V CD45 populations (Fig. 2 ). Annexin-V 0 99.8 0.1 0.73 99 Pharmacokinetic studies of the OVA conjugate demonstrated 0101 102 103 0101 102 103 that ERY1-OVA erythrocyte binding was long-lived in vivo, OVA binding exhibiting a cell surface t1/2 of 17.2 h (Fig. 2C). ERY1-OVA remained bound to erythrocytes for as long as 72 h following 2.0 150 ∼ C fluorescence intensity fluorescence administration; during this time frame, 13% of erythrocytes are ERY1-OVA mean geometric OVA cleared in the mouse (17). Quantification of erythrocyte-bound 1.5 OVA 100 OVA 1.0 A OVA ERY1-OVA B t1/2 = 17.2 h 6 50 1. SMCC OVA ERY1 OVA concentration OVA 0.5 (ng/10 erythrocytes) 2. ERY1-Cys ERY1 GYPA ERY1 ERY1 ERY1 0 0 ERY1-OVA 20 40 60 80 170150 ERY1 glycophorin-A Time post injection (h) OVA Fig. 2. ERY1-conjugated antigen biospecifically binds circulating healthy and erythrocyte eryptotic erythrocytes on i.v. administration, inducing uptake by specific APC GYPA subsets. (A) OVA (gray-filled histogram) and ERY1-OVA (black-filled histo- − gram) binding to erythrocyte (CD45 ) and nonbinding to leukocyte (CD45+) C D populations in vivo compared with noninjected mice (empty histogram), 100 100 ERY1-OVA determined by flow cytometry.
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