Vitiligo lesions can be treated with antibodies, but off-target effects may be harmful. Injection with a bispecific antibody returns pigmentation only to the area of injection and limits systemic side effects.
- Vitiligo, an autoimmune condition, can be treated with immunosuppressant drugs.
- Local injection of skin lesions is preferable to systemic treatment because off-target side effects can harm the rest of the body.
- Keratinocytes are the major contributor to vitiligo lesions.
- A bispecific antibody was developed that tethers to keratinocytes and restores pigmentation around the site of injection without impacting distal tissue.
Vitiligo is an autoimmune condition characterized by depigmentation of melanocytes in the skin. Progression of vitiligo lesions is related to interferon-gamma (IFN-γ) signaling, which promotes destruction of melanocytes and expands lesioned areas. Treatments can effectively neutralize the actions of IFN-γ and reduce vitiligo severity, but systemic delivery causes unwanted side effects. A new, more targeted, approach to neutralizing IFN-γ is being developed to treat lesions locally without off-target effects.
Targeting IFN-γ in Keratinocytes
The IFN-γ pathway predominantly takes place in keratinocytes (KCs), where harmful chemokines are produced that promote vitiligo. KCs in the basal layer of the epidermis are the primary cells that amplify IFN-γ signaling and the main source of CXCR3-ligand chemokines in vitiligo, creating positive feedback mechanisms that continue the production of IFN-γ and activity of CD8+ T cells. In a recent animal model study published in the Journal of Investigative Dermatology, scientists tested a bispecific antibody that will specifically tether to KCs and neutralize IFN-γ.
Bispecific Antibody Improved Vitiligo Lesions With Fewer Systemic Effects
In mice with vitiligo, the bispecific antibody effectively inhibited IFN-γ signaling on KCs and improved vitiligo lesions at the site of footpad injection. Pigmentation did not return in other parts of the skin. Compared to a non-specific antibody, the experimental treatment demonstrated better skin retention, more localized effects, less systemic IFN-γ inhibition, and faster clearing from the blood. Tethering the antibody for IFN-γ neutralization to KCs limits the treatment effects to the desired area, which is a desirable quality for an immunosuppressant antibody.
The Importance of Targeted Treatments for Vitiligo
Patients with vitiligo typically present with depigmentation on more than 20% of their skin. Targeted treatments are necessary because inhibiting IFN-γ throughout the whole body results in severe side effects. With the bispecific antibody targeting KCs, the treatment is effectively tethered to the site of injection. Future therapeutics for vitiligo will benefit from targeted approaches to limit negative off-tissue effects.
Hsueh, Y. C., Wang, Y., Riding, R. L., Catalano, D. E., Lu, Y. J., Richmond, J. M., Siegel, D. L., Rusckowski, M., Stanley, J. R., & Harris, J. E. (2022). A Keratinocyte-Tethered Biologic Enables Location-Precise Treatment in Mouse Vitiligo. J Invest Dermatol, 142(12), 3294-3303. https://doi.org/10.1016/j.jid.2022.06.007