Could the GI tract be a better portal for antibody therapy?

Reinisch and colleagues (Gut 2006;55:1138–44) recently reported that the infusion of fontolizumab, an anti‐interferon γ antibody, into patients with Crohn's disease was generally well tolerated with encouraging clinical responses. Unfortunately, not all first trials with therapeutic antibodies go as well as planned. As we recently witnessed with the intravenous administration of TGN1412, designed to activate regulatory T cells for the treatment of leukaemia and autoimmune diseases such as rheumatoid arthritis, six volunteers were hospitalised, four of whom suffered major organ failure. The patients' conditions was described as “cytokine release syndrome” which occurs when activated T cells produce a systemic inflammatory response.

Could the violent reaction to the monoclonal antibody be avoided with oral administration? Ochi et al's recent report may offer an answer. They observed that oral was as effective as intravenous administration of anti‐CD3 in reversing established experimental autoimmune encephalomyelitis.¹

While traditionally administered intravenously, when anti‐CD3 was administered orally it was found to be effective and to have fewer side effects. Because antibodies are not well absorbed in the gastrointestinal tract, they do not enter the bloodstream where they might otherwise stimulate circulating T cells to release the proinflammatory cytokines that are often associated with adverse events.

In many ways, similar to TGN1412, anti‐CD3 also interacts with a subset of regulatory T cells on administration with the intent to suppress autoimmunity. On ingestion, anti‐CD3 was found to survive passage through the gastrointestinal tract functionally intact, and was subsequently taken up into the Peyer's path in the luminal wall of the small intestine. There, anti‐CD3 initiated a cascade of events outside of the gastrointestinal tract, leading to activation of regulatory T cells. These newly activated T cells migrated via the bloodstream to distal lymph nodes of autoimmune inflammation and suppressed the pathogenic T cells contributing to disease.

This complex cascade of events all began with ingestion of antibodies. Anti‐CD3 survived the long passage through the harsh gut environment to find the appropriate portal in the small intestine to trigger the cascade of events. This outcome has significant implications that will likely reach beyond experimental encephalomyelitis and extend to other autoimmune inflammatory conditions found both locally within the gastrointestinal tract and systemically.

It is therefore somewhat surprising that of the 18 approved monoclonal antibodies, only one is administered outside of the bloodstream. Furthermore, there do not appear to be any monoclonals or therapeutic antibodies in late stage clinical trials intended for oral administration.

Chatenoud's opening comments in a review on oral administration of anti‐CD3 reminds us that modern medicine continues to work under the assumption that therapeutic proteins, such as antibodies, are simply ineffective when administrated orally because of degradation in the digestive tract. Unfortunately, this prevailing assumption is carried over to both development and clinical practice where we continue to design and administer such biotherapeutics intravenously.²

Have we created a biopharmaceutical industry that is dependent on the needle to deliver biologicals? We currently live in an era of protein design, molecular targeting, and humanising therapeutic proteins to overcome potential side effects associated with intravenously administration.

The fact remains, however, that not only do antibodies survive pancreatic enzymes and low pH environments, they retain functionality after passage through the gastrointestinal tract of both infants and adults.³,⁴ Animal models have demonstrated that orally delivered antibodies prevented rotavirus and cholera infections. Also, multiple human clinical trials have demonstrated that oral delivery of bovine antibodies were extremely effective in preventing rotavirus, enterogenic E coli, shigella infection, and necrotising enterocolitis.⁴

It is interesting to note that antibodies and other beneficial biologicals such as cytokine cocktails have been delivered in mother's milk for eons and have evolved to survive the harsh gut environment, ensuring their arrival to the mucosal lining of the gastrointestinal tract. These naturally occurring biologicals afford protection against a number of gastrointestinal pathogens, including rotavirus, E coli, shigella, Crytosporidium, C difficile, and H pylori, among others. They also protect us against a number of inflammatory bowel conditions, including ulcerative colitis, Crohn's disease, non‐steroidal anti‐inflammatory drug induced gut injury, and chemotherapy induced mucositis.⁵,⁶

In light of the clinical outcome of TGN1412, these recent observations about anti‐CD3 should provoke a rethinking of the needle for many promising biologicals. Also, in the case of dose escalation of fontolizumab in future trials, flu‐like symptoms and chills may be non‐existent with even more encouraging outcomes with oral administration.