Trough levels of ipilimumab in serum as a potential biomarker of clinical outcomes for patients with advanced melanoma after treatment with ipilimumab

Abstract

BackgroundImmune checkpoint blockade (ICB) using anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of advanced cancer. However, ICB is effective for only a small fraction of patients, and biomarkers such as expression of PD-L1 in tumor or serum levels of CXCL11 have suboptimal sensitivity and specificity. Exposure–response (E-R) relationships have been observed with other therapeutic monoclonal antibodies. There are many factors influencing E-R relationships, yet several studies have shown that trough levels of anti-PD-1/PD-L1 correlated with clinical outcomes. However, the potential utility of anti-CTLA-4 levels as a biomarker remains unknown.MethodsSerum was obtained at trough levels at weeks 7 and 12 (after doses 2 and 4) from patients with advanced melanoma who received ipilimumab alone (3 mg/kg every 3 weeks for four treatments) via an expanded access program (NCT00495066). We have successfully established a proteomics assay to measure the concentration of ipilimumab in serum using an liquid chromatography with tandem mass spectrometry-based nanosurface and molecular-orientation limited proteolysis (nSMOL) approach. Serum samples from 38 patients were assessed for trough levels of ipilimumab by the nSMOL assay.ResultsWe found that trough levels of ipilimumab were higher in patients who developed immune-related adverse events but did not differ based on the presence or absence of disease progression. We found that patients with higher trough levels of ipilimumab had better overall survival when grouped based on ipilimumab trough levels. Trough levels of ipilimumab were inversely associated with pretreatment serum levels of CXCL11, a predictive biomarker we previously identified, and soluble CD25 (sCD25), a prognostic biomarker for advanced melanoma, as well as C reactive protein (CRP) and interleukin (IL)-6 levels at week 7.ConclusionsOur results suggest that trough levels of ipilimumab may be a useful biomarker for the long-term survival of patients with advanced melanoma treated with ipilimumab. The association of ipilimumab trough levels with pretreatment serum levels of CXCL11 and sCD25 is suggestive of a baseline-driven E-R relationship, and the association of ipilimumab trough levels with on-treatment levels of CRP and IL-6 is suggestive of response-driven E-R relationship. Our findings highlight the potential utility of trough levels of ipilimumab as a biomarker.Trial registration numberNCT00495066.

A rapid and universal liquid chromatograph-mass spectrometry-based platform, refmAb-Q nSMOL, for monitoring monoclonal antibody therapeutics

“…TDMbased therapeutic guidance is becoming widely utilized in clinical practice for patients losing response to anti-TNF agents for inflammatory bowel diseases 27 . We and others showed that the trough levels of ICI mAb can be a biomarker for cancer immunotherapy 3,4,[8][9][10] , this is of particular importance given the relatively low predictive capability of current biomarkers such as anti-PD-L1 IHC and TMB 14 . Therefore, development of a universal platform for quantitative analysis of mAbs is essential to streamline the PK study, TDM for effective use of mAbs, and biomarker discovery.…”

“…Major advantages of the refmAb-Q nSMOL assay stem from its backbone, the nSMOL assay. We have applied and validated the nSMOL assay for more than 40 mAbs including 2 Fc fusion proteins 8,9,21,46-48 . The exquisite specificity of mAbs and availability of 6 CDR legions (3 from each heavy and light chains) enables robust selection of the signature peptide as we and others have demonstrated 30 .…”

“…Serum samples were obtained from patients with advanced melanoma who received ipilimumab 9,22 , pembrolizumab 8 , or combination of ipilimumab and nivolumab. All patients provided written informed consent and all studies were carried out in accordance with the Declaration of Helsinki under good clinical practice and Institutional Review Board approval.…”

“…Monitoring of mAb levels is critical for drug development to ensure safety and efficacy of mAbs [3][4][5] . Therapeutic drug monitoring (TDM), used for small molecule drugs, has been applied to adjust the doses of mAbs for patients with chronic inflammatory immune disease 6,7 In addition, we and others have demonstrated that the trough levels of ICIs may serve as a potential biomarker for the effectiveness of cancer immunotherapy [8][9][10][11][12][13] . This is of particular note as current biomarkers for prediction of ICI response such as PD-L1 immunohistochemistry (IHC) and tumor mutational burden (TMB) profiling are imperfect, and a minority of treated individuals exhibit a significant tumor response to the therapy 14 .…”

A rapid and universal liquid chromatograph-mass spectrometry-based platform, refmAb-Q nSMOL, for monitoring monoclonal antibody therapeutics

“…Therapeutic drug monitoring (TDM), used for small molecule drugs, has been applied to adjust the doses of mAbs for patients with chronic inflammatory immune disease 6,7 . In addition, we and others have demonstrated that the trough levels of ICIs may serve as a potential biomarker for the effectiveness of cancer immunotherapy [8][9][10][11][12][13] . This is of particular note as current biomarkers for prediction of ICI response such as PD-L1 immunohistochemistry (IHC) and tumor mutational burden (TMB) profiling are imperfect, and a minority of treated individuals exhibit a significant tumor response to the therapy 14 .…”