Abstract
Immunotherapy has changed the paradigm of cancer treatments. In this way, several combinatorial strategies based on monoclonal antibodies (mAb) such as anti (a)-PD-1 or anti (a)-PD-L1 are often reported to yield promising clinical benefits. However, the pharmacokinetic (PK) behavior of these mAbs is a critical issue that requires selective analytical techniques. Indeed, few publications report data on a-PD1/a-PD-L1 exposure and its relationship with therapeutic or toxic effects. In this regard, preclinical assays allow the time profiles of antibody plasma concentrations to be characterized rapidly and easily, which may help to increase PK knowledge. In this study, we have developed and validated two in-house ELISAs to quantify a-PD-1 and a-PD-L1 in plasma collected from tumor-bearing mice. The linear range for the a-PD-1 assay was 2.5–125 ng/mL and 0.11–3.125 ng/mL for the a-PD-L1 assay, whereas the intra-and inter-day precision was lower than 20% for both analytes. The PK characterization revealed a significant decrease in drug exposure after administration of multiple doses. Plasma half-life for a-PD-1 was slightly shorter (22.3 h) than for a-PD-L1 (46.7 h). To our knowledge, this is the first reported preclinical ELISA for these immune checkpoint inhibitors, which is sufficiently robust to be used in different preclinical models. These methods can help to understand the PK behavior of these antibodies under different scenarios and the relationship with response, thus guiding the choice of optimal doses in clinical settings.
Highlights
Therapeutic monoclonal antibodies represent one of the most promising strategies to treat different types of diseases, including cancer [1]
Cancer immunotherapy based on the modulation of the immune system using certain monoclonal antibodies (mAb) has substantially contributed to achieving relevant clinical outcomes [3]
This work aims to develop and validate two easy-to-use enzyme-linked immunosorbent assay (ELISA) to quantify a-Programmed Death-1 receptor (PD-1) and a-PD-L1 plasma concentrations collected from tumor-bearing mice and determine the PK profiles and main parameters of these agents
Summary
Therapeutic monoclonal antibodies (mAb) represent one of the most promising strategies to treat different types of diseases, including cancer [1] In this context, mAbs against certain upregulated molecules in cancer cells and the tumor microenvironment have opened up new mechanisms to achieve tumor regression [2]. Cancer immunotherapy based on the modulation of the immune system using certain mAbs has substantially contributed to achieving relevant clinical outcomes [3]. In this regard, immune checkpoints (ICs) such as Programmed Death-1 receptor (PD-1) and its endogenous ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), have been shown to be validated targets for cancer treatments [4].
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