Specificity of the T Cell Response to Protein Biopharmaceuticals

Abstract

The anti-drug antibody (ADA) response is an undesired humoral response raised against protein biopharmaceuticals (BPs) which can dramatically disturb their therapeutic properties. One particularity of the ADA response resides in the nature of the immunogens, which are usually human(ized) proteins and are therefore expected to be tolerated. CD4 T cells initiate, maintain and regulate the ADA response and are therefore key players of this immune response. Over the last decade, advances have been made in characterizing the T cell responses developed by patients treated with BPs. Epitope specificity and phenotypes of BP-specific T cells have been reported and highlight the effector and regulatory roles of T cells in the ADA response. BP-specific T cell responses are assessed in healthy subjects to anticipate the immunogenicity of BP prior to their testing in clinical trials. Immunogenicity prediction, also called preclinical immunogenicity assessment, aims at identifying immunogenic BPs and immunogenic BP sequences before any BP injection in humans. All of the approaches that have been developed to date rely on the detection of BP-specific T cells in donors who have never been exposed to BPs. The number of BP-specific T cells circulating in the blood of these donors is therefore limited. T cell assays using cells collected from healthy donors might reveal the weak tolerance induced by BPs, whose endogenous form is expressed at a low level. These BPs have a complete human sequence, but the level of their endogenous form appears insufficient to promote the negative selection of autoreactive T cell clones. Multiple T cell epitopes have also been identified in therapeutic antibodies and some other BPs. The pattern of identified T cell epitopes differs across the antibodies, notwithstanding their humanized, human or chimeric nature. However, in all antibodies, the non-germline amino acid sequences mainly found in the CDRs appear to be the main driver of immunogenicity, provided they can be presented by HLA class II molecules. Considering the fact that the BP field is expanding to include new formats and gene and cell therapies, we face new challenges in understanding and mastering the immunogenicity of new biological products.

Pegylation Reduces the Uptake of Certolizumab Pegol by Dendritic Cells and Epitope Presentation to T-Cells

“…Immunogenicity incidence of Certolizumab pegol appears to be variable across studies depending on the sensitivity of the assays (16)(17)(18) but the ADA response was mainly characterized by low titers and by an effect on PK for highest titers, only (https://www.ema.europa.eu). In line with the clinical immunogenicity, CD4 T-cell epitopes have been identified in many of these antibodies (19)(20)(21)(22) and underlined the role of mutations with respect to the germline sequences to drive the Tcell response (20)(21)(22). Evaluation of the size of the specific T-cell repertoire before injection of the BPs using healthy donors also showed a good concordance with clinical immunogenicity (13,21,23,24).…”

Anti-brolucizumab immune response as one prerequisite for rare retinal vasculitis/retinal vascular occlusion adverse events

“…Most likely, the numbers of patients investigated (only five RV/RO-positive and six RV/RO-negative patients) were too low to determine an HLA class II restriction, and a larger dataset would be needed to better understand a possible correlation. Furthermore, the extent of the response could potentially be modulated by various factors, such as co-medication, cytokine profiles, or immune cell composition, specifically the abundance of regulatory T cells and follicular T helper cell subpopulations ( 17 , 18 ).…”

Conformational Stability and Denaturation Processes of Proteins Investigated by Electrophoresis under Extreme Conditions

“…Engineered covalent modifications of proteins such as “capping” with polyethylene glycol, polysialic acid, or other polymeric shells and encapsulation into nanocontainers have proved to considerably increase the stability of pharmaceutical proteins [ 12 ], to increase their residence time in blood after injection, and to prevent adverse immune responses to injected free or nanoencapsulated heterologous proteins [ 13 , 14 ].…”