Anti-CD3 oral immunotherapy employs a monoclonal antibody (MAb), directed against the CD3 molecule on the surface of T cells. Injected anti-CD3 (aCD3) MAb was indicated for preventing transplant rejection, but it could induce serious adverse effects that precluded wide clinical use. The model for down-regulation of certain immune responses is that man is generally immunologically tolerant to food and natural gut bacteria as a result of immunological activities in gut-associated lymphoid tissues (GALT). Based on this, it was observed subsequently in animal models that oral administration of aCD3 MAb results in the induction of regulatory T cells (Tregs) in the GALT that circulate systemically and can mediate the suppression of inflammatory and autoimmune diseases and thus confer efficacy in preventing induction or progression of disease in a range of animal models of inflammatory and autoimmune diseases. These models include immune-mediated hepatitis, non-alcoholic steatohepatitis or fatty liver (NASH), type-2 diabetes (T2D), type-I diabetes (T1D), experimental auto-immune encephalitis, lupus, colitis, arthritis, cardiac allograft rejection, and atherosclerosis. In a Phase 1 clinical study, groups of healthy adults were administered different daily oral aCD3 regimens for five days. The MAb regimens were found to be safe and well tolerated, free of significant adverse effects, and without any indication of generalized immune suppression. Furthermore, the aCD3 MAb regimens were found to induce transient changes in immunological markers consistent with the induction of Tregs and of anti-inflammatory immune responses, which are associated with efficacy in animal models.
An initial Phase 2a clinical trial was conducted in subjects with NASH and the metabolic syndrome in which groups of nine subjects received one of three aCD3 MAb dosage levels or placebo once daily for 30 days. Oral aCD3 immunotherapy was found to be safe and well-tolerated, and induced positive trends in clinical biomarkers and immunological markers in groups receiving oral aCD3 but not in the placebo group – some of these trends were statistically significant in spite of the very small group sizes. These positive effects were reduced blood levels of two enzymes that are biomarkers for liver inflammation which is a favorable outcome for subjects with NASH, and reduced blood levels of glucose and triglycerides and improved performance in glucose tolerance testing which is a favorable outcome for subjects with T2D or altered glucose metabolism. Changes also were observed in immunological markers consistent with the induction of Treg cells and of anti-inflammatory immune responses, and correlations were found between some favorable immunological changes and clinical biomarker changes.
A second Phase 2a clinical trial with the same trial design and size was conducted in subjects with chronic hepatitis C. Oral aCD3 immunotherapy was found to be safe and well-tolerated, and induced positive trends in clinical biomarkers and immunological markers in groups receiving oral aCD3 MAb but not in the placebo group – some of these trends also were statistically significant. These positive effects were reduced blood levels of two enzymes that are biomarkers for liver inflammation and reduced levels of hepatitis C virus, both of which are favorable outcomes for subjects with chronic hepatitis C. Changes also were observed in immunological markers consistent with the induction of Treg cells and of anti-inflammatory immune responses, and correlations were found between some favorable immunological changes and clinical biomarker changes.
A Phase 2a clinical trial as an Investigator IND study is ongoing in the US for subjects with ulcerative colitis.
A new MAb has been developed and is being produced at high expression levels in a cell line suitable for scaleup and GMP production.