Autoimmune and allergic diseases occur when an individual mounts an inappropriate immune response to a self-antigen or an innocuous environmental antigen. This triggers a pathogenic T-cell response resulting in damage to specific tissues and organs. In type 1 diabetes (T1D), this manifests as destruction of the insulin-secreting β cells, resulting in a life-long dependency on recombinant insulin. Modulation of the pathogenic T-cell response with antigen-specific peptide immunotherapy offers the potential to restore the immune homeostasis and prevent further tissue destruction. Recent clinical advances with peptide therapy approaches in both T1D and other diseases are beginning to show encouraging results. New technologies targeting the peptides to specific cell types are also moving from pre-clinical development to the clinic. While many challenges remain in clinical development, not least selection of the optimal dose and dosing frequency, this is clearly becoming a very active field of drug development.
Type 1 diabetes (T1D) is an organ-specific autoimmune disease. Auto-reactive T cells attack the insulin-producing beta (β) cells of the pancreatic islets, leading to a loss of endogenous insulin production and subsequent impaired glucose metabolism. Management of the disease requires daily administration of exogenous insulin and frequent monitoring of blood glucose levels. While there have been significant advances in recombinant human insulins and technologies both to deliver insulin and monitor blood glucose levels, many patients do not achieve optimal glycemic control. This is particularly apparent in children and young adults, in whom blood glucose control, measured by glycated hemoglobin (HbA1c) levels, is typically poor, reaching greater than 8% in the majority when the desired levels are below 7.5%. The longer-term complications associated with elevated levels of HbA1c are significant and include retinopathy, nephropathy, and neuropathy. Clearly, there is a need for new therapies that either preserve or restore β-cell function to improve glycemic control and patient outcomes.
Preservation of an individual’s own endogenous insulin secretion by modulation of the immune system would be the optimal solution. However, the major challenge for this therapeutic approach is that at the time of diagnosis, a considerable loss of β cells has already occurred. Encouragingly, there are now supportive data to suggest that preservation of residual β-cell function at the time of diagnosis may indeed lead to improvements in glycemic control and thereby impact upon long-term outcomes. Preventing immune-mediated attack on β cells would also open the possibility for β-cell regeneration and/or replacement therapies to be more effective and durable.
Autoimmune and allergic diseases arise when an individual mounts an inappropriate immunological response to a self-antigen or an innocuous environmental antigen. Antigen-reactive T cells become activated and expand in number, and the regulatory T-cell pool is no longer capable of controlling the immune response, leading to the loss of immune homeostasis. Peptide immunotherapy offers the potential to restore immune homeostasis via the expansion of the regulatory T-cell pool and the deletion and/or anergy of the pathogenic T-cell population.
Clinical proof of concept that peptide therapy can restore immune homeostasis has been championed by studies of allergic disease. Cat-PAD is a peptide cocktail consisting of seven peptides from Feld1, the major cat allergen. A recent clinical study has shown that a short course of intra-dermal treatment with these peptides resulted in a clinically meaningful reduction in rhino-conjunctivitis symptoms, 2 years post-treatment. Disappointingly, a large phase III study failed to confirm the earlier positive clinical data. This may in part be explained by a large placebo effect that was observed and the transition to field-based studies, which inherently introduce greater variability. An ongoing clinical study focusing on the phenotype of the allergen-specific T cells following administration of Cat-PAD will confirm whether peptide therapy can modulate the pathogenic T-cell response.
Clinical studies with peptides derived from auto-antigens for the treatment of autoimmune disease are also now emerging. A phase IIa study with a peptide immunotherapy treatment for relapsing remitting multiple sclerosis demonstrated statistically significant reductions in total and new T1 Gadolinium enhancing brain lesions (representing sites of inflammation and damage) measured using magnetic resonance imaging during treatment. This therapy consists of a cocktail of four peptides derived from myelin basic protein. Two recent phase I studies with a peptide immunotherapy treatment for celiac disease have also shown encouraging data suggesting that the antigen-specific T-cell responses can be modulated following peptide treatment. Further development of NexVax2, a mix of three peptides derived from gluten, is planned.
For peptide therapy to be successful in treating autoimmune or allergic disease, it is essential that the major auto-antigens responsible for driving the disease are known. Using the presence of auto-antibodies to the same antigens as a guide increases the probability that appropriate antigens have been selected. The ability to detect antigen-specific T cells is also important not only to aid the initial epitope discovery of disease-relevant peptides but also to track modulation of the T-cell phenotype following clinical administration.
Type 1 diabetes emerges as an ideal autoimmune disease for trialing treatment with peptide therapy. A number of the major antigens have been identified, including proinsulin, GAD65, IA-2, and ZnT8. Auto-antibodies to these antigens can be detected both in the sera of patients at the time of diagnosis and in individuals who are at high risk of future disease, whether they are entirely asymptomatic with no signs of disease, or have early indications of impaired glucose tolerance. Antigen-specific T cells from the blood of patients and at-risk subjects can be detected and, indeed, exhibit a proinflammatory cytokine response upon antigen stimulation ex vivo. It is appealing to propose that progression of disease toward diabetes in high-risk subjects will be more tractable to therapies such as peptide administration than the scenario of waiting for the disease to become established. In the future, this will need to be tested in multiple antibody-positive non-diabetic subjects, whose risk of disease development over a lifetime approaches 100%.
An early clinical study in T1D patients administered an altered peptide ligand (APL) derived from the insulin B9-23 epitope (NBI-6024) showed some initial promise. Modulation of the antigen-specific T-cell response from a predominantly IFNγ response to a more Th2 bias was detected. However, a subsequent clinical study powered to assess the effect of repeated administrations of NBI-6024 on endogenous insulin production, as measured by C-peptide levels in adult and adolescent patients with new-onset T1D, failed to demonstrate any clinical benefit.
In parallel to the clinical development of NBI-6024, a natural peptide sequence derived from proinsulin was also under evaluation. An initial phase 1 safety study in patients with long-standing diabetes and low c-peptide levels (<200 pmol/L) compared three monthly intra-dermal injections of 10 versus 100 µg of the C19-A3 peptide. The peptide was shown to be well tolerated and safe. In addition, as was observed in the initial NBI-6024 study, there was a trend toward modulation of the antigen-specific T-cell response with an apparently increased frequency of IL-10 producing cells in the low-dose treatment group.
Subsequently, a second clinical study with the single proinsulin peptide was conducted in newly diagnosed patients and the results have recently been reported. In this study, monthly versus fortnightly intra-dermal injections of 10 µg of peptide were compared, over a period of 6 months. The peptide was shown to be well tolerated and safe. Although the study was not powered to examine efficacy at the level of preservation of β-cell function, there was evidence in some patients on the active treatment that the rate of decline in secreted c-peptide slowed and daily insulin use and HbA1c stabilized. Intriguingly, these subjects who could be labeled “treated c-peptide responders” also showed immunological changes compared with non-responders on active treatment, including greater propensity for CD4 T-cell production of IL-10 upon ex vivo stimulation and enhanced expression of the canonical regulatory T cell transcription factor FoxP3 on peripherally generated, adaptive regulatory T cells post-therapy. These findings, linking clinical and immunological outcome provide an encouraging platform on which to build strategies for biomarkers of peptide immunotherapy.
The clinical studies described thus far, both in T1D and the other indications, have focused on either a single peptide to modulate the pathogenic T cell response or multiple peptides from the same antigen. A different approach, using multiple peptides from two different auto-antigens linked to the pathogenesis of T1D, is currently being evaluated as a treatment for new-onset T1D patients. This phase Ib tolerability and safety study evaluating monthly intra-dermal injections of a cocktail of multiple peptides should provide new insights when data become available in 2018.
A slightly different peptide therapy approach to those previously described is also under clinical evaluation. The approach is to take a natural peptide derived from one of the major auto-antigens linked to T1D and modify it slightly to improve its affinity. These modified peptides are known as Imotopes™. Injection of the Imotopes™ is believed to elicit antigen-specific cytolytic CD4 T cells that induce lysis of antigen-presenting cells (APCs) with which a synapse is formed, as well as the auto-antigen-specific bystander T cells, activated on the surface of the same APC. A phase Ib safety and tolerability study is currently underway, exploring three different doses administered sub-cutaneously in alum, with study completion expected December 2018.
The peptide therapy approaches leading the way in clinical development for both T1D and other autoimmune diseases are relatively simple. The peptides are administered either intra-dermally or sub-cutaneously in the absence of any additional substantial modifications. Whether these approaches are sufficient to bring significant clinical benefit in large phase III clinical studies remains to be seen, but certainly, the promise peptide therapy holds for restoration of immune regulation has led a number of pharmaceutical companies to develop novel and innovative ways to target the peptides in a more specific manner for potentially enhanced efficacy. These include targeting of peptides to the erythrocyte, encapsulating peptides into nanoparticles and encapsulating peptides into liposomes with α-GalCer. A highly novel approach being developed involves coating peptide-MHC complexes onto nanoparticles to generate “navacims”. As yet, there are no data to indicate which method of peptide delivery will be optimal and bring the greatest clinical benefit, but clearly this is a fast evolving field.
While peptide therapy for T1D is clearly entering an exciting phase of drug development, there are still a number of unanswered questions and challenges, not least whether the approach will bring real clinical benefit. Selecting the optimal dose of peptide and optimal dosing interval is one key challenge. This is in part because it is difficult to study both the kinetics of peptide uptake and the bio-distribution of peptides. Access to better immunological tools to track
