Immunogenicity of immunomodulatory, antibody-based, oncology therapeutics

Abstract

The increasing use of multiple immunomodulatory (IMD) agents for cancer therapies (e.g. antibodies targeting immune checkpoints, bispecific antibodies, and chimeric antigen receptor [CAR]-T cells), is raising questions on their potential immunogenicity and effects on treatment. In this review, we outline the mechanisms of action (MOA) of approved, antibody-based IMD agents, potentially related to their immunogenicity, and discuss the reported incidence of anti-drug antibodies (ADA) as well as their clinical relevance in patients with cancer. In addition, we discuss the impact of the administration route and potential strategies to reduce the incidence of ADA and manage treated patients. Analysis of published reports indicated that the risk of immunogenicity did not appear to correlate with the MOA of anti-programmed death 1 (PD-1)/PD-ligand 1 monoclonal antibodies nor to substantially affect treatment with most of these agents in the majority of patients evaluated to date. Treatment with B-cell depleting agents appears associated with a low risk of immunogenicity. No significant difference in ADA incidence was found between the intravenous and subcutaneous administration routes for a panel of non-oncology IMD antibodies. Additionally, while the data suggest a higher likelihood of immunogenicity for antibodies with T-cell or antigen-presenting cell (APC) targets versus B-cell targets, it is possible to have targets expressed on APCs or T cells and still have a low incidence of immunogenicity. Electronic supplementary material The online version of this article (10.1186/s40425-019-0586-0) contains supplementary material, which is available to authorized users.

Economics of alternative dosing strategies for pembrolizumab and nivolumab at a single academic cancer center

“…PD‐1 antibodies are also immunogenic. Treatment with immune checkpoint inhibitors can result in the development of antidrug antibodies, including antibodies with the potential to neutralize the binding of the checkpoint inhibitor to its ligand although they are currently of unclear clinical significance …”

“…Treatment with immune checkpoint inhibitors can result in the development of antidrug antibodies, including antibodies with the potential to neutralize the binding of the checkpoint inhibitor to its ligand although they are currently of unclear clinical significance. 32 Several caveats to the strategies of vial sharing and dose minimization require examination. Cost analyses did not consider the increased drug preparation time (estimated at 3-5 minutes per patient dose) in our pharmacy.…”

Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications

“…An issue with utilizing chimeric mAbs for therapy is potential immunogenicity. Studies have shown the risk of immunogenicity is lower with humanized mAbs versus chimeric mAbs (20). The chimeric mAbs in this comparison contained murine variable domains, and it is not known whether chimeric mAbs with rabbit variable domains have comparable immunogenicity.…”

Recent progress in the molecular imaging of therapeutic monoclonal antibodies

“…Maintaining appropriate levels of mAbs ensures sufficient contact with antigens (e.g., the driving force for diffusion into the tumor) and the subtherapeutic concentrations of mAbs is proposed to cause the inefficacy or acquired resistance [ 45 ]. Also, some mAb drugs have immunogenicity and will stimulate the body to produce antibodies against them, called anti-drug antibody (ADA), to increase their clearance [ 46 ]. Therefore, monitoring mAbs in vivo is pivotal for the best therapeutic outcome.…”