Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders

Abstract

Monoclonal antibody (mAb) therapy was first established upon the approval of a mouse antibody for treatment of human acute organ rejection. However, the high incidence of immune response against the mouse mAb restricted therapeutic utility. Development of chimeric, "humanized" and human mAbs broadened therapeutic application to immune-mediated diseases requiring long-term treatment. Indeed, mAb therapeutics targeting soluble cytokines are highly effective in numerous immune-mediated disorders. A recent example is ustekinumab, a first-in-class therapeutic human immunoglobulin G1 kappa mAb that binds to the interleukins (IL)-12 and IL-23, cytokines that modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets. Ustekinumab was generated via recombinant human IL-12 immunization of human immunoglobulin (hu-Ig) transgenic mice. Ustekinumab binds to the p40 subunit common to IL-12 and IL-23 and prevents their interaction with the IL-12 receptor β1 subunit of the IL-12 and IL-23 receptor complexes. Ustekinumab is approved for treatment of moderate-to-severe plaque psoriasis and has demonstrated efficacy in Crohn disease and psoriatic arthritis. The clinical characterization of ustekinumab continues to clarify our understanding of human immune pathologies and may offer a novel therapeutic option for certain immune-mediated diseases.

Figure 1

Function of interleukin (IL)-12 and IL-23 on effector cells. IL-12-specific specific effects are designated red; IL-23-specific effects are designated green. Properties attributed to both IL-12 and IL-23 are designated blue. CXCL, chemokine (C-X-C) motif; IFNγ, interferon gamma; GMCSF, granulocyte macrophage colony stimulating factor; NKT, natural killer cells; TNFα, tumor necrosis factor. Cited from references , , – and .

Figure 2

Human antibody transgenic mice. Human heavy and light chain genes were used by GenPharm (later known as Medarex, now part of Bristol-Meyers Squibb) to prepare minilocus human immunoglobulin (hu-Ig) transgenic mice (HC4/KCo5). Mice were immunized with human interleukin-12 (IL-12) to produce human antibodies. H, heavy; κ, kappa; ms, mouse.

Figure 3

Ustekinumab discovery, cell line generation and antibody production. Ustekinumab is a human monoclonal antibody (mAb) discovered through the generation of hybridoma cultures from immunized human immunoglobulin (hu-Ig) transgenic (Tg) mice. Hybridomas secreting human mAbs that neutralized interleukin-12 (IL-12) were identified. Ustekinumab variable (V) and constant (C) domains were cloned from hybridoma cells and the heavy (H) and light (L) chains of the V and C domains were transfected into new host cells by electroporation. Ustekinumab is produced using perfusion fermentation culture and purified from the supernatant generated from the fermentation process.

Figure 4

Ustekinumab mechanism of action. Ustekinumab binds to the p40 subunit of interleukin (IL)-12 and IL-23 and prevents their interaction with the cell surface IL-12Rβ1 receptor, subsequently inhibiting IL-12- and IL-23-mediated cell signaling, activation and cytokine production (image not drawn to scale). NK, natural killer. Adapted from Benson et al.

Figure 5

Proposed model for psoriasis immunopathogenesis. Activated dendritic cells (DCs) induce differentiation of naive T cells into effector cells such as T-helper (Th) 1 and Th17 cells, which then release effector cytokines that induce the production of chemokines and adhesion receptors on endothelial cells. Effector cells infiltrate the skin and contribute to keratinocyte activation and proliferation. The overall result is a continuing cycle of T cell and DC activation resulting in the maintenance of psoriatic skin inflammation and plaque formation. Reproduced with permission from Nestle et al.

Figure 6

Proposed central role of interleukin (IL)-12/23 and T helper (Th)1/17 cells in psoriasis, psoriatic arthritis, Crohn disease and sarcoidosis pathologies. Observations to date from clinical studies with ustekinumab suggest common immune pathways between psoriasis, psoriatic arthritis and Crohn disease. The role of IL-12/23 in sarcoidosis is under evaluation.