OX40 in the Pathogenesis of Atopic Dermatitis-A New Therapeutic Target

Abstract

Atopic dermatitis (AD) is a chronic, heterogeneous, inflammatory disease characterized by skin lesions, pruritus, and pain. Patients with moderate-to-severe AD experience chronic symptoms, intensified by unpredictable flares, and often have comorbidities and secondary complications, which can result in significant clinical burden that impacts the patient's overall quality of life. The complex interplay of immune dysregulation and skin barrier disruption drives AD pathogenesis, of which T-cell-dependent inflammation plays a critical role in patients with AD. Despite new targeted therapies, many patients with moderate-to-severe AD fail to achieve or sustain their individual treatment goals and/or may not be suitable for or tolerate these therapies. There remains a need for a novel, efficacious, well-tolerated therapeutic option that can deliver durable benefits across a heterogeneous AD patient population. Expression of OX40 [tumor necrosis factor receptor superfamily, member 4 (TNFRSF4)], a prominent T-cell co-stimulatory molecule, and its ligand [OX40L; tumor necrosis factor superfamily, member 4 (TNFSF4)] is increased in AD. As the OX40 pathway is critical for expansion, differentiation, and survival of effector and memory T cells, its targeting might be a promising therapeutic approach to provide sustained inhibition of pathogenic T cells and associated inflammation and broad disease control. Antibodies against OX40 [rocatinlimab (AMG 451/KHK4083) and telazorlimab (GBR 830)] or OX40L [amlitelimab (KY1005)] have shown promising results in early-phase clinical studies of moderate-to-severe AD, highlighting the importance of OX40 signaling as a new therapeutic target in AD.

Fig. 1

Involvement of OX40 in local and systemic inflammation in atopic dermatitis. Evidence supports that OX40 expression may drive both local and systemic inflammation in patients with atopic dermatitis. AD, atopic dermatitis; CD, cluster of differentiation; IL, interleukin; OX40, OX40 receptor; OX40L, OX40 ligand; Th, T helper cell.

Fig. 2

Role of OX40 signaling in atopic dermatitis pathogenesis. Square textboxes present an overview of the inflammatory response in atopic dermatitis skin lesions. In atopic dermatitis, expression of OX40 on effector T cells is hypothesized to be induced early by skin barrier disruption and sustained by prolonged expression of proinflammatory cytokines [83, 84]. OX40L is expressed on the surface of activated antigen presenting cells such as Langerhans cells and dendritic cells and other cells (not shown in the figure) such as type 2 innate lymphoid cells, mast cells, and keratinocytes [85, 86, 88]. Round textboxes present the key aspects of atopic dermatitis pathogenesis hypothesized to be driven and sustained by OX40 signaling. The OX40 pathway is believed to play a central role in T-cell expansion, effector function development, and subsequent memory T-cell formation, which drives local and systemic inflammation of AD [12, 83, 84, 87, 95]. AD, atopic dermatitis; IL, interleukin; OX40, OX40 receptor; OX40L, OX40 ligand; Th, T helper cell; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin.