Abstract
Monoclonal antibodies (mAbs) are a leading class of biotherapeutics. In oncology, patients often fail on early lines of biologic therapy to a specific target. Some patients may then enroll in a new clinical trial with a mAb specific for the same target. Therefore, immunoassays designed to quantify the current mAb therapy or assess immunogenicity to the drug may be susceptible to cross-reactivity or interference with residual prior biologics. The impact of two approved anti-PD-1 mAbs, pembrolizumab and nivolumab, was tested in several immunoassays for cemiplimab, another approved anti-PD-1 mAb. The methods included a target-capture drug concentration assay, a bridging anti-drug antibody (ADA) assay and a competitive ligand-binding neutralizing antibody (NAb) assay. We also tested bioanalytical strategies to mitigate cross-reactivity or interference in these assays from other anti-PD-1 biologics. Both pembrolizumab and nivolumab cross-reacted in the cemiplimab drug concentration assay. This was mitigated by addition of antibodies specific to pembrolizumab or nivolumab. ADA specific for pembrolizumab and nivolumab did not interfere in the cemiplimab ADA assay. However, pembrolizumab and nivolumab generated a false-positive response in a target-capture NAb assay. Our results demonstrate that similar exogenous pre-existing anti-PD-1 mAbs (biotherapeutics) such as pembrolizumab and nivolumab are detected and accurately quantified in the cemiplimab drug concentration assay. However, once steady state is achieved for the new therapy, prior biologics would likely not be detected. Cross-reactivity and interference in immunoassays from previous treatment with class-specific biotherapeutic(s) pose significant bioanalytical challenges, especially in immuno-oncology.Graphical abstract
Highlights
Biotherapeutics and especially monoclonal antibodies are one of the fastest growing segments of the pharmaceutical industry [1]
Since the cemiplimab drug concentration assay uses PD-1 as the capture reagent, and a non-specific anti-IgG4 as the detection reagent, we investigated the potential for these two similar anti-PD-1 therapies to interfere with or cross-react in the cemiplimab drug concentration or immunogenicity assays [14, 16, 17]
We demonstrated that pembrolizumab, nivolumab, or anti-drug antibodies to either of these monoclonal antibodies (mAbs) do not interfere in the cemiplimab bridging anti-drug antibody (ADA) assay
Summary
Biotherapeutics and especially monoclonal antibodies (mAbs) are one of the fastest growing segments of the pharmaceutical industry [1]. Two therapeutic areas in particular have witnessed rapid growth in recent years: cancer immunotherapies, Vol.:(0123456789) AAPS J (2021) 23:109 referred to as immuno-oncology (IO), and immunology and inflammatory diseases (I&I, e.g., anti-TNF-α) [2, 3]. This has resulted in an increasingly competitive and crowded treatment landscape. Hundreds of biotherapeutics engaging the same targets are under investigation in clinical studies (see Table I) [4, 5] This redundancy is likely beneficial for both patients and health care providers as it provides multiple therapeutic options. In the last few years, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved seven immune check point inhibitors (CPIs): one monoclonal antibody targeting the CTLA-4 pathway (ipilimumab), three targeting PD-L1 (atezolizumab, avelumab and durvalumab), and four targeting PD-1 (cemiplimab, dostarlimab, nivolumab, and pembrolizumab), for the treatment of patients with multiple cancer types [8,9,10]
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