The Epitope-Specific Anti-human CD4 Antibody MAX.16H5 and Its Role in Immune Tolerance

Abstract

T cell modulation in the clinical background of autoimmune diseases or allogeneic cell and organ transplantations with concurrent preservation of their natural immunological functions (e.g., pathogen defense) is the major obstacle in immunology. An anti-human CD4 antibody (MAX.16H5) was applied intravenously in clinical trials for the treatment of autoimmune diseases (e.g., rheumatoid arthritis) and acute late-onset rejection after transplantation of a renal allograft. The response rates were remarkable and no critical allergic problems or side effects were obtained. During the treatment of autoimmune diseases with the murine MAX.16H5 IgG 1 antibody its effector mechanisms with effects on lymphocytes, cytokines, laboratory and clinical parameters, adverse effects as well as pharmacodynamics and kinetics were studied in detail. However, as the possibility of developing immune reactions against the murine IgG 1 Fc-part remains, the murine antibody was chimerized, inheriting CD4-directed variable domains of the MAX.16H5 IgG 1 connected to a human IgG 4 backbone. Both antibodies were studied in vitro and in specific humanized mouse transplantation models in vivo with a new scope. By ex vivo incubation of an allogeneic immune cell transplant with MAX.16H5 a new therapy strategy has emerged for the first time enabling both the preservation of the graft-vs.-leukemia (GVL) effect and the permanent suppression of the acute graft-vs.-host disease (aGVHD) without conventional immunosuppression. In this review, we especially focus on experimental data and clinical trials obtained from the treatment of autoimmune diseases with the murine MAX.16H5 IgG 1 antibody. Insights gained from these trials have paved the way to better understand the effects with the chimerized MAX.16H5 IgG 4 as novel therapeutic approach in the context of GVHD prevention.

Humanized mouse model: Hematopoietic stemcell transplantation and tracking using short tandem repeat technology

“…After a minimum of 4 hours of recovery time, 2 × 10 5 or 4 × 10 5 CD34 + HSC were injected intrahepatically. The transplantation of PBMC was carried out by intravenous injection of 2 × 10 7 cells (preincubated with or without anti-human CD4 antibody MAX.16H5 IgG 4 to suppress the graft-vs-host reaction potentially mediated by the graft, a concept which we already described earlier 4,13,14 ). PB samples were obtained by retrobulbar bleeding under anesthesia.…”

Non-genotoxic conditioning facilitates hematopoietic stem cell gene therapy for hemophilia A using bioengineered factor VIII

“… 60 , 61 , 62 Similar to the mAb cocktail used in the current study, these drugs clear host T cells and may be effective in our HSCT gene therapy protocol. Alternatively, investigational mAbs that specifically target CD4 (e.g., MAX.16H5 63 , 64 or IT1208 65 ) or CD3 66 (e.g., teplizumab, otelixizumab, visilizumab, or foralumab) might be considered. A similar approach to that taken in a recent phase 1/2 clinical trial of HSC-directed LV gene therapy for the primary immunodeficiency Wiskott-Aldrich syndrome, in which fludarabine and rituximab (CD20 mAb) were used to achieve immune cell depletion prior to transplantation, could be pursued.…”

The Potential Genes Mediate the Pathogenicity of Allogeneic CD4+T Cell in aGVHD Mouse Model

“…Studies have shown that the regulation of donor-derived CD4 + T cells and the production of some critical cytokines (such as IFN- γ ) could affect the development of aGVHD [ 5 ]. CD4 + T cells have been studied as the potential treatment targets for GVHD in a large number of clinical trials [ 4 , 6 ]. A clinical study, however, found that peripheral blood stem cell (PBSC) graft containing more mature T cells did not increase the incidence and severity of aGVHD [ 7 ].…”