Have we overestimated the benefit of human(ized) antibodies?

Abstract

The infusion of animal-derived antibodies has been known for some time to trigger the generation of antibodies directed at the foreign protein as well as adverse events including cytokine release syndrome. These immunological phenomena drove the development of humanized and fully human monoclonal antibodies. The ability to generate human(ized) antibodies has been both a blessing and a curse. While incremental gains in the clinical efficacy and safety for some agents have been realized, a positive effect has not been observed for all human(ized) antibodies. Many human(ized) antibodies trigger the development of anti-drug antibody responses and infusion reactions. The current belief that antibodies need to be human(ized) to have enhanced therapeutic utility may slow the development of novel animal-derived monoclonal antibody therapeutics for use in clinical indications. In the case of murine antibodies, greater than 20% induce tolerable/negligible immunogenicity, suggesting that in these cases humanization may not offer significant gains in therapeutic utility. Furthermore, humanization of some murine antibodies may reduce their clinical effectiveness. The available data suggest that the utility of human(ized) antibodies needs to be evaluated on a case-by-case basis, taking a cost-benefit approach, taking both biochemical characteristics and the targeted therapeutic indication into account.

Figures and Tables

Figure 1 Immunogenicity of monoclonal antibodies. There are numerous mechanisms that may account for the immunogenicity of monoclonal antibodies. Importantly, many of these phenomena act synergistically, potentiating life-threatening immune responses. In the case of anti-CD3 antibodies such as OKT3, the antibody can bind to the CD3 receptor freely, or in the context of antigen-presenting cells (APCs) through Fc receptor binding. This presentation cross-links the CD3 molecule on the T-cell surface, triggering immunoreceptor tyrosine-based activation motif (ITAM)-mediated T-cell activation. In the case of some human antibodies, complementarity-determining regions may also be presented to the T cells in the context of major histocompatibility complex. No matter the form of T-cell presentation, all trigger ITAM-mediated cytokine production. Some cytokines, including interleukin (IL)-2, act in a positive feedback loop on the T cells, causing further T-cell activation, proliferation and cytokine production. Other cytokines, such as tumor necrosis factor (TNF), mediate febrile responses and, in conjunction with interferon (IFN)γ, activate APCs, which may produce their own set of pro-inflammatory cytokines. In addition to APC activation, IFNγ also stimulates affinity maturation in B cells, also known as class switching. Initially, B cells will produce transient low-affinity antibodies, with little to no clinical relevance. However, cytokines such as IFNγ drive B cells to produce antibodies with high affinity. In the context of protein therapeutics, these antibodies are usually IgG antibodies that may exhibit long serum half lives and neutralizing properties.

Table 1 Human(ized) and rodent derived antibodies that have been tested in humans