Advanced Drug Delivery Reviews 98 (2016) 86–98 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Combining antigen and immunomodulators: Emerging trends in antigen-specific immunotherapy for autoimmunity ☆ Laura Northrup a, Matthew A. Christopher a, Bradley P. Sullivan a, Cory Berkland a,b,⁎ a Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA b Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, KS 66045, USA article info abstract Article history: A majority of current therapies for autoimmune diseases are general immunosuppressants, which can compromise Received 1 August 2015 patient response to opportunistic infection and lead to adverse events. Using antigen-specificimmunotherapy Received in revised form 23 October 2015 (ASIT) to selectively disarm autoimmune diseases, without suppressing the global immune response, would be Accepted 26 October 2015 a transformative therapy for patients. ASIT has been used historically in allergy hyposensitization therapy to Available online 3 November 2015 induce tolerance to an allergen. Similar strategies to induce immune tolerance toward autoantigens responsible Keywords: for autoimmune disease have been attempted but have yielded limited clinical success. Recent studies of ASIT for Autoimmunity autoimmunity have explored combination therapy, combining the disease-causing autoantigen with an immu- Antigen-specific immunotherapy nomodulatory compound. ASIT combination therapy may direct the immune response in an antigen-specific Combination therapy manner, potentially reversing the root cause of autoimmunity while limiting side effects. This review analyzes Co-administration recent advances in ASIT applied to autoimmune diseases, emphasizing current combination therapies and future Co-delivery strategies. © 2015 Elsevier B.V. All rights reserved. Contents 1. Introduction...............................................................87 2. Introductiontoautoimmunediseases....................................................88 2.1. Immunetoleranceandregulatoryresponses.............................................88 2.2. Immunologyofautoimmunity....................................................88 2.3. Autoimmunediseases.......................................................88 3. Currenttherapiesforautoimmunity....................................................89 3.1. Generalimmunosuppressants....................................................89 3.2. Mobilitiyandtransportinhibitors..................................................90 3.3. Immunecellactivationinhibitors..................................................90 3.4. Antigenicmimics..........................................................90 3.5. Currentcombinationtherapiesforautoimmunedisease........................................91 4. CombinationstrategiesforASITinautoimmunity..............................................91 4.1. Co-administration.........................................................91 4.1.1. Co-administrationwithsmallmoleculeimmunosuppressants.................................91 4.1.2. Co-administrationwithbiologicalmolecules.........................................91 4.1.3. Drawbacksofco-administration...............................................92 4.2. Co-delivery............................................................92 4.2.1. Co-deliverywithsmallmoleculeimmunosuppressants....................................92 4.2.2. Co-deliverywithpeptides.................................................93 4.2.3. Co-deliverywithbiologicalmolecules............................................93 5. ClinicaltrialsofASITforautoimmunity...................................................93 5.1. Antigen-onlyASITclinicaltrials...................................................93 5.2. CombinationASITclinicaltrials...................................................93 ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Therapeutics for Synergistic Therapy.” ⁎ Corresponding author at: Department of Pharmaceutical Chemistry, University of Kansas, 2030 Becker Drive, 320E, Lawrence, KS 66047, USA. E-mail address: [email protected] (C. Berkland). http://dx.doi.org/10.1016/j.addr.2015.10.020 0169-409X/© 2015 Elsevier B.V. All rights reserved. L. Northrup et al. / Advanced Drug Delivery Reviews 98 (2016) 86–98 87 6. ChallengesforthefutureofASITforautoimmunity............................................. 94 6.1. Humantranslationofpre-clinicalsuccesses............................................. 94 6.2. Antigen identificationandepitopespreading............................................. 94 6.3. Immunomodulatoroptimization.................................................. 94 6.4. Co-deliveryvehicle........................................................ 95 6.5. Routeofadministration...................................................... 95 7. Conclusion................................................................ 96 Acknowledgements.............................................................. 96 References.................................................................. 96 1. Introduction downstream effects. For example, rapamycin (Sirolimus) has tradition- ally been considered an immunosuppressant drug; however, recently, it Antigen-specific immunotherapy (ASIT) has been used in the clinic has been discovered that the mammalian target of rapamycin (mTOR) for over a century to induce antigen-specific immune responses. pathway is essential in maintaining the balance between tolerance Vaccines were the first approach to direct an antigen-specificimmune and inflammation [11]. Immunomodulation in the treatment of autoim- response, utilizing disease-causing antigens in order to induce prophy- munity, therefore, extends far beyond immunosuppression and can in- lactic protective immune responses against specific foreign pathogens. volve shifting the immune response toward tolerance through a variety Treatments with specific allergy-inducing antigens have also been use- of mechanisms (Table 1). Unfortunately, the lack of antigen-specificity ful for the induction of antigen-specific immune tolerance for allergy in immunomodulation can lead to undesired side effects and potentially desensitization. Clinical treatment of autoimmune diseases, however, increase the risk of opportunistic infections in patients taking these im- still relies primarily on global immune suppression through the use munosuppressive therapies. of potent small molecule immunomodulators. Within the last decade, One promising strategy in the creation of ASIT for autoimmunity is scientists have more deeply explored combinations of immunomodu- combination therapy of antigen and immunomodulator. This strategy lators and autoantigens in the hope of creating effective ASIT for the mimics the successful “antigen-adjuvant” model used in the creation treatment of autoimmune diseases, a strategy that could substantially of vaccines. Adjuvants are immunomodulators used in vaccines to en- improve clinical outcomes without compromising the entire immune hance the antigen-specific immune response, increasing the potency system. of the vaccine. Applying this paradigm for treating autoimmune disease, One of the most successful strategies in ASIT for inducing immune the combination of antigen and immunomodulator may be able to di- tolerance has been the use of hyposensitization therapy in the treat- rect the immune response toward tolerance to autoantigen. ment of allergies. Hyposensitization therapy has been used since the This review highlights recent work combining immunomodulators early 1900s as a means to desensitize patients to specific allergens [1]. with autoantigen either by co-administration or co-delivery to induce tol- In the seminal papers published by Noon [2] and Freeman [3] in 1911, erance in autoimmune disease. We present a thorough background on pollen extracts were injected subcutaneously using an increasing-dose the immunological processes involved in autoimmunity and tolerance, schedule in order to relieve symptoms from grass pollen allergy and along with an examination of currently approved therapies. Recent ex- hay fever [1]. The current “gold standard” for hyposensitization therapy perimental work utilizing co-administration and co-delivery techniques, is surprisingly similar to these techniques described over a century ago combining antigen and immunomodulator, have shown exciting new [1]. Although hyposensitization for allergies has been effective in many promise in autoimmune therapy. ASIT combination therapies have also cases, several disadvantages have yet to be remedied. The dosing sched- shown promise in the clinic. With the recent advances in ASIT, the poten- ule is often difficult for patients to complete due to the frequency and tial to induce antigen-specific tolerance to treat, prevent, or possibly cure length of the therapy [1]. The majority of hyposensitization therapy is a subset of autoimmune diseases in humans may be on the horizon. given via subcutaneous injections and needs to be administered by a trained professional over a period of years [1,4]. Sublingual ASIT may ul- Table 1 timately increase treatment convenience; however, the most important Mechanisms of action for autoimmune therapies. consideration, safety, may remain an issue [4]. Unfortunately, in some cases, hyposensitization therapy can become life threatening as anaphy- Mechanism of action Drug example laxis can occur following treatment