Ingested (oral) rituximab inhibits EAE.

BACKGROUND: Blocking CD20 can inhibit autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). OBJECTIVE: We examined whether an antibody against CD20, rituximab (RTX) (Rituxan®), used clinically in oncology, MS and RA would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or RTX during ongoing disease. Splenocytes or CD4(+) T cells from control fed or RTX fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. Actively fed and recipient mice were examined for disease inhibition, inflammation, and cytokine responses. RESULTS: Ingested (oral) RTX inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from RTX fed donors protected against actively induced disease and decreased inflammation. There was a decrease in Th1-like cytokines IFN-γ and IL-12, IL-17 and TNF-α in active fed and adoptively treated recipients without upregulation of counter-regulatory cytokines. CONCLUSIONS: Ingested (orally administered) RTX can inhibit disease, CNS inflammation, decrease pro-inflammatory IL-17 and Th1-like cytokines without increases in Th2-like anti-inflammatory cytokines.

Ingested (oral) tocilizumab inhibits EAE.

BACKGROUND: Blocking the activity of IL-6 can inhibit autoimmune diseases such as rheumatoid arthritis and Crohn's disease. OBJECTIVE: We examined whether an antibody against IL-6, tocilizumab (TCZ) (Actemra®), used clinically in rheumatoid arthritis (RA) would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHOD: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or TCZ during ongoing disease. Splenocytes, CD4(+) T cells or macrophages/monocyte lineage cells (CD11b(+)) from control fed or TCZ fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. Actively fed and recipient mice were examined for disease inhibition, inflammation, and cytokine responses. RESULTS: Ingested (oral) TCZ inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from TCZ fed donors protected against actively induced disease and decreased inflammation. There was a decrease in IL-6 in actively treated spleen, decrease in TNF-α, Th1-like cytokine IL-12 and increase in Th2-like cytokine IL-10 in active fed and adoptively treated recipients. CONCLUSIONS: Ingested (orally administered) TCZ can inhibit disease, CNS inflammation, decrease pro-inflammatory Th1-like cytokines and increase Th2-like anti-inflammatory cytokines.

Challenges and opportunities in delivering oral peptides and proteins.

INTRODUCTION: Rapid advances in bioengineering enable the use of complex proteins as therapeutic agents to treat diseases. Compared with conventional small molecule drugs, proteins have multiple advantages, including high bioactivity and specificity with low toxicity. Developing oral dosage forms with active proteins is a route to improve patient compliance and significantly reduce production costs. However, the gastrointestinal environment remains a challenge to this delivery path due to enzymatic degradation, low permeability, and weak absorption, leading to reduced delivery efficiency and poor clinical outcomes. AREAS COVERED: This review describes the barriers to oral delivery of peptides and complex proteins, current oral delivery strategies utilized and the opportunities and challenges ahead to try and circumvent these barriers. Oral protein drugs on the market and clinical trials provide insights and approaches for advancing delivery strategies. EXPERT OPINION: Although most current studies on oral protein delivery rely on in vitro and in vivo animal data, the safety and limitations of the approach in humans remain uncertain. The shortage of clinical data limits the development of new or alternative strategies. Therefore, designing appropriate oral delivery strategies remains a significant challenge and requires new ideas, innovative design strategies and novel model systems.

Advances in formulation and manufacturing strategies for the delivery of therapeutic proteins and peptides in orally disintegrating dosage forms.

Therapeutic proteins and peptides (TPPs) are increasingly favoured above small drug molecules due to their high specificity to the site of action and reduced adverse effects resulting in increased use of these agents for medical treatments and therapies. Consequently, there is a need to formulate TPPs in dosage forms that are accessible and suitable for a wide range of patient groups as the use of TPPs becomes increasingly prevalent in healthcare settings worldwide. Orally disintegrating dosage forms (ODDF) are formulations that can ensure easy-to-administer medication to a wider patient population including paediatrics, geriatrics and people in low-resource countries. There are many challenges involved in developing suitable pharmaceutical strategies to protect TPPs during formulation and manufacturing, as well as storage, and maintenance of a cold-chain during transportation. This review will discuss advances being made in the research and development of pharmaceutical and manufacturing strategies used to incorporate various TPPs into ODDF systems.

Ingested ACTH blocks Th17 production by inhibiting GALT IL-6.

BACKGROUND: EAE is an inflammatory autoimmune process of the CNS that resembles multiple sclerosis (MS) and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. Oral ACTH (adrenocorticotropic hormone) can decrease clinical disease, IL-17 and Th1-like encephalitogenic IFN-γ secretion and increase Treg frequency. The mechanism by which oral ACTH decreases inflammatory proteins and increases Treg cell frequencies is unknown. OBJECTIVE: IL-6 is a pivotal cytokine in the gut that determines the relative frequencies of Th17 vs Treg cells. We examined whether oral ACTH inhibited IL-6 in the gut associated lymphoid tissue (GALT) in EAE. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with scrambled ACTH (scrambled melanocyte stimulating hormone [scrambled α-MSH]) or ACTH 1-39 during ongoing disease. RESULTS: Ingested (oral) ACTH inhibited ongoing clinical disease. In the lamina propria (LP) immune compartment, there were significantly less CD11b + IL-6 and IL-17 producing lymphocytes from ACTH fed mice compared to s-MSH fed mice. There was also a decrease in the frequency of IL-17 and IFN-γ producing spleen cells and an increase in CD4 + FoxP3+ Treg cell frequency in ACTH fed mice compared to s-MSH fed control spleens. There were less IFN-γ producing CNS lymphocytes in ACTH fed mice compared to s-MSH fed control CNS. CONCLUSIONS: Ingested ACTH inhibits EAE clinical disease by inhibiting IL-6 in the GALT.

Ingested (oral) anti-IL-12/23 inhibits EAE.

BACKGROUND: Blocking the activity of IL-12/23 can inhibit autoimmune diseases such as psoriasis. OBJECTIVE: We examined whether an antibody against IL-12/23, ustekinumab (UTZ) (Stelera®), used clinically in psoriasis would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with isotype IgG control or UTZ during ongoing disease. Splenocytes, CD4(+) T cells or macrophages/monocyte lineage cells (CD11b(+)) from control fed or UTZ fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. Actively fed and recipient mice were examined for disease inhibition, inflammation, and cytokine responses. RESULTS: Ingested (oral) UTZ inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from UTZ fed donors protected against actively induced disease and decreased inflammation. Oral UTZ decreased pro-inflammatory cytokines Th1-like cytokines IL-2, IL-12, IFN-γ, IL-17 (Teff) and TNF-α in UTZ fed mice and increased counter-regulatory cytokines IL-4, IL-10 and IL-13 in recipients of donor cells from UTZ fed mice. CONCLUSIONS: Ingested (orally administered) UTZ can inhibit disease, CNS inflammation, decrease pro-inflammatory Th1-like and Th17 cytokines and increase Th2-like anti-inflammatory cytokines.