Is there potential for the approval of monoclonal antibodies to treat thyroid-associated ophthalmopathy?

1. Introduction

Thyroid-associated ophthalmopathy (TAO, aka Graves’ orbitopathy or thyroid eye disease) represents the ocular manifestation of thyroid autoimmunity, most commonly occurring in Graves’ disease (GD) [1, 2]. It is a disfiguring and potentially blinding process that substantially diminishes the quality of life of those with moderate to severe disease. While the thyroid dysfunction associated with GD is treated with relative ease and is most often associated with predictably favorable outcomes, the medical and surgical therapies for TAO are currently inadequate. These poor options result in large part from our incomplete understanding of disease pathogenesis and the historical absence of high-fidelity animal models. Another substantial barrier to therapy development for TAO is its relative rarity and heterogeneous clinical presentation. Here I attempt to identify molecular targets in TAO against which monoclonal antibody approaches for therapy have been attempted.

2. Initial examination of anti-CD20 mAbs as B cell depleting agents

Exploration of new treatments for GD and TAO entered the biological age with the initial studies involving rituximab, an anti-CD20 mAb [3–5]. Rituximab was developed more than 20 years ago as therapy for relapse/refractory CD20⁺ non-Hodgkin B cell lymphomas [6]. In the last 10 years, it has found an important place in the therapeutic armamentarium of several autoimmune diseases, including neuromyelitis optica [7]. It has achieved U.S. FDA registration for rheumatoid arthritis, Wegener’s granulomatosis, microscopic polyangiitis, and granulomatosis with polyangiitis [8]. Two recent, small clinical trials in moderate to severe TAO examined the effects of rituximab. One study compared rituximab to methylprednisolone and found that the latter was superior in improving clinical activity [9]. The other study, which was placebo-controlled, detected no difference in disease activity in either treatment arm [10]. Neither study revealed improvement in proptosis. Thus further evaluation of rituximab in TAO will be required before any definitive conclusions can be drawn as to its efficacy in the disease.

2.1. TSHR/IGF-IR receptor complex

At the heart of GD is the loss of immune tolerance to the thyrotropin receptor (TSHR) and generation of activating antibodies against this receptor protein, known as thyroid-stimulating immunoglobulins (TSI) [2, 11]. While this receptor is the central autoantigen in the hyperthyroidism of GD, its role and that of TSIs in TAO is substantially less well-defined. Strong circumstantial evidence supports the involvement of TSI in TAO (reviewed in Smith and Janssen, 2018) [12]; however, many details concerning how TSHR and TSI participate in the pathogenesis of the process remain to be elucidated. Clearly, reports have surfaced suggesting that levels of TSI might correlate with disease activity and predict whether patients might develop severe disease in the future [13]. In addition to TSHR, another cell surface receptor has been implicated in TAO and may represent a useful therapeutic target. The insulin-like growth factor-I receptor (IGF-IR) has also been insinuated in TAO [12 14 15]. Like TSHR, many of the aspects of its involvement in TAO are as yet uncertain. Much of the uncertainty of either receptor’s role in the disease results from the vast majority of experimental evidence coming from studies performed in vitro [14–20]. Antibodies generated in GD appear to be involved in driving the orbital tissue reactivity and remodeling found in TAO by inducing the production of proinflammatory cytokines and the synthesis of hyaluronan [18 20]. In aggregate, they are referred to hereafter as GD immunoglobulin G (GD-IgG), whether the activities are attributable to TSI or to a distinct, anti-IGF-IR antibody. Modifying their interactions with orbital autoantigens or altering the signaling events that result from these antibody-antigen interactions seems to represent potentially useful therapeutic targets. The specificities of effects resulting from receptor inhibition may differ from those therapeutically targeting/interrupting post-receptor signaling. Besides the activating antibodies targeting TSHR and IGF-IR, the two receptors have been found to form a physical and functional signaling complex [15]. Importantly, inhibiting IGF-IR activity in target cells (fibroblasts, fibrocytes or thyroid epithelial cells) results in attenuated signaling initiated by both receptors [15]. Since this signaling culminates in the induction of several genes that appear to participate in disease pathogenesis, it was proposed that interrupting the IGF-I pathway might represent a useful strategy for treating TAO [21]. Recent studies conducted in vitro have demonstrated powerful attenuation of TSHR-initiated induction of cytokine induction [22 23].

Several molecules that target TSHR, including mAbs and small molecules, have been developed and recently reviewed [24 25]. The suitability of these agents as therapeutics remains untested in clinical trials. With regard to IGF-IR, several mAbs have been developed and a number subjected to clinical trials examining their efficacy in various types of cancer [26]. Despite disappointing results concerning their therapeutic benefit, these agents generally exhibited satisfactory safety profiles. One such drug, teprotumumab, was repurposed for treatment of moderate to severe, active TAO [27]. Teprotumumab blocks binding of IGF-I and IGF-II to IGF-IR as well as promoting its internalization. It is a functional inhibitor of IGF-IR and appears to act as a β-arrestin biased agonist of IGF-IR. Teprotumumab was assessed in a multicenter, placebo-controlled trial [27]. That study disclosed unprecedented effectiveness of the mAb in reducing proptosis, clinical activity, and diplopia. On the basis of the recently reported initial study, teprotumumab has been designated by the US FDA as breakthrough therapy for TAO.

2.2. Cytokines as therapeutic targets in TAO

Besides TSHR and IGF-IR, a number of proinflammatory cytokines and the signaling pathways lying upstream from their generation and downstream from their respective receptors, have been identified as potentially involved in the pathogenesis of TAO. Among these, the IL-6 pathway appears to be involved in several autoimmune diseases. IL-6 is an abundant molecule that promotes the polarization of T cells toward the Th17 paradigm in concert with TGF-β, IL-1β, and IL-23 [28]. In GD-OF, TSH and TSI enhance substantially the expression and release of IL-6 [18]. A small study of the IL-6 receptor blocking mAb, tocilizumab, administered to 18 patients with steroid-resistant, active TAO disclosed encouraging results; however, the trial was uncontrolled and preliminary in nature [29]. A very recent follow-up study including 32 patients with moderate to severe TAO were randomized to tocilizumab or placebo and found to have met the primary response of ≥2 points of clinical activity [30]. As a general concept, interrupting cytokine networks appears to be potentially effective in autoimmune diseases, especially given the success with several agents targeting TNF-α in rheumatoid arthritis, psoriasis and related diseases [31]. Considerably more investigation will be required to fully assess the effectiveness and safety of anti-cytokine drugs in TAO.

3. Conclusions

Several proposed approaches to improve the medical treatment of active, moderate to severe TAO involve the use of monoclonal antibodies. These target molecules are currently thought to be involved in disease pathogenesis. Most agents have been repurposed from other diseases. Among the most encouraging is teprotumumab, an inhibitory antibody against IGF-IR. Results from a recently concluded clinical study strongly suggest its remarkable effectiveness and encouraging safety profile. Teprotumumab has been designated a “breakthrough” therapy for TAO and is currently undergoing evaluation in a confirmatory phase 3 study.