Frequency Of Anti-drug Antibodies Research Articles

Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine

Biologic drugs have greatly improved treatment outcomes of inflammatory joint diseases, but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. Anti-drug antibodies influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. The prevalence of ADAb differs among drugs and diseases, and the detection of ADAb also depends on the assay format. Most data exist for the tumor necrosis factor-alpha inhibitors infliximab and adalimumab, with a frequency of ADAb that ranges from 10 to 60% across studies. Measurement of ADAb and serum drug concentrations, therapeutic drug monitoring, has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by therapeutic drug monitoring, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates the development of cut-offs necessary for guidelines and the implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost effectiveness exist to support therapeutic drug monitoring as a routine clinical strategy to monitor biologic drugs in inflammatory joint diseases. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of inflammatory joint diseases.

Monitoring of infliximab treatment in inflammatory bowel diseases – basic knowledge and current data based on clinical trials in a population of Polish patients

Introduction and aim. Infliximab is the oldest biological drug belonging to the group of tumor necrosis factor antagonists. Despite the availability of many new biological therapies, this drug still plays an important role in the treatment of inflammatory bowel diseases. However, a significant problem related to pharmacotherapy is the high inter-individual variability of the response. Material and methods. This study presents results of the research on the treatment with infliximab in the inflammatory bowel disease (IBD) patients including our own experience in Polish IBD patients. Analysis of the literature. Therapeutic failure while using infliximab can be attributed partly to inadequate serum concentrations of the drug and the development of anti-drug antibodies. Many studies have attempted to find a relationship between the specific level of infliximab and the achieved healing effect. These analyses show that the optimal level of the drug differs depending on the type of disease, its phenotype, and therapeutic goal and that the optimization of infliximab therapy remains an open topic. Two studies involving the population of Polish IBD patients examined the level of infliximab during and after induction, as well as the frequency of anti-drug antibodies. Two studies involving a population of Polish IBD patients examined the level of infliximab during and after induction, as well as the frequency of anti-drug antibodies. These studies demonstrated the need for monitoring infliximab treatment at weeks 6 and 14. Conclusion. Reactive monitoring is believed to enable the most rational treatment decisions; however, experts also recommend that proactive monitoring should measure infliximab concentrations at the end of induction and at least once during maintenance treatment.

Serum golimumab concentration and anti-drug antibodies are associated with treatment response and drug survival in patients with inflammatory joint diseases: data from the NOR-DMARD study

Objectives: This study aimed to identify the therapeutic target concentration and frequency of anti-drug antibodies (ADAbs) in golimumab-treated patients with inflammatory joint disease (IJD). Method: Associations between golimumab concentration, ADAbs, and treatment response were examined in 91 patients with IJD [41 axial spondyloarthritis (axSpA), 20 rheumatoid arthritis (RA), and 30 psoriatic arthritis (PsA)] included in the NOR-DMARD study. Treatment response was defined by Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement in axSpA, European League Against Rheumatism (EULAR) good/moderate response in RA, and improvement of ≥ 50% in modified Disease Activity index for PSoriatic Arthritis (DAPSA) (28 swollen/tender joint counts) in PsA. Serum drug concentrations and ADAbs were analysed using automated in-house assays. Results: At inclusion, 42% were biological disease-modifying anti-rheumatic drug naïve and 42% used concomitant synthetic disease-modifying anti-rheumatic drug. The median golimumab concentration was 2.2 (interquartile range 1.0–3.5) mg/L. The proportions of responders after 3 months among patients with golimumab concentration < 1.0, 1.0–3.9, and ≥ 4.0 mg/L were 19%, 49%, and 74%, respectively. A higher rate of treatment discontinuation was seen in patients with serum golimumab concentration < 1.0 compared to ≥ 1.0 mg/L (hazard ratio 3.3, 95% confidence interval 1.8–6.0, p < 0.05). ADAbs were detected in 6%, and were associated with lower drug concentrations and both reduced treatment response and drug survival. Conclusions: Golimumab concentrations ≥ 1.0 mg/L were associated with improved treatment response and better drug survival, although some patients may benefit from higher concentrations. This study suggests a rationale for dosing guided by therapeutic drug monitoring in golimumab-treated patients with IJD. The results should be confirmed in larger studies including trough samples, and the efficacy of such a strategy must be examined in randomized controlled trials.

EP19 Renal sarcoidosis associated with certolizumab pegol treatment for psoriatic arthritis: a case report

EP19 Renal sarcoidosis associated with certolizumab pegol treatment for psoriatic arthritis: a case report

A Phase I Study of CC-90002, a Monoclonal Antibody Targeting CD47, in Patients with Relapsed and/or Refractory (R/R) Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndromes (MDS): Final Results

A Phase I Study of CC-90002, a Monoclonal Antibody Targeting CD47, in Patients with Relapsed and/or Refractory (R/R) Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndromes (MDS): Final Results

Anti-CD47 Antibody, CC-90002, in Combination with Rituximab in Subjects with Relapsed and/or Refractory Non-Hodgkin Lymphoma (R/R NHL)

Anti-CD47 Antibody, CC-90002, in Combination with Rituximab in Subjects with Relapsed and/or Refractory Non-Hodgkin Lymphoma (R/R NHL)

DMD CLINICAL THERAPIES I: P.123A randomized, placebo-controlled, double-blind, phase 1b/2 study of the novel anti-myostatin adnectin RG6206 (BMS-986089) in ambulatory boys with Duchenne muscular dystrophy

Inhibition of myostatin, a negative regulator of muscle growth, has been shown to increase skeletal muscle mass in several species. RG6206 (BMS-986089) is a potent, novel anti-myostatin adnectin shown to inhibit myostatin activity in healthy adults. This phase 1b/2 study (NCT02515669) assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RG6206 in ambulatory boys with Duchenne muscular dystrophy (DMD). Forty-three ambulatory boys with DMD, aged 5-10, were randomized to receive weekly subcutaneous RG6206 (4-50 mg) or placebo. The primary endpoint was safety and tolerability over 24 weeks. Secondary endpoints were PK of RG6206, frequency of anti-drug antibodies (ADAs), effect on serum myostatin levels and MRI imaging. Exploratory outcomes included 4-stair climb velocity (4SC), 6-minute walk test distance (6MWT) and DXA imaging. No clinically significant changes in laboratory values, vital signs or ECG parameters were observed. Adverse events (AEs) were mostly mild; the most common drug-related AE was mild-to-moderate cutaneous injection site reactions (n=7, 21.9%). ADAs were observed in one patient, who had a positive titer at baseline with no post-treatment boost. RG6206 serum concentrations increased with dose and were accompanied by dose-dependent reduction in free myostatin at all dose levels. RG6206 was well tolerated. DXA imaging data showed increased lean body mass with RG6206 treatment vs. placebo. MRI imaging of the right thigh suggested that RG6206 had positive effects on muscle composition, with an increase in contractile, and lesser increase in non-contractile, tissue compared with placebo. However, this response did not appear to be dose dependent. Post hoc analyses of the correlation between MRI/DXA imaging data and functional measures including 4SC and 6MWT will be presented. An ongoing 48-week open-label phase of this study and a Phase 2/3 study will further evaluate RG6206 in ambulatory boys with DMD (NCT03039686).

Correlation between HLA haplotypes and the development of antidrug antibodies in a cohort of patients with rheumatic diseases.

IntroductionThe aim of this study was to investigate the correlation between human leukocyte antigen (HLA) haplotypes and the development of antidrug antibodies (ADAs) in a cohort of patients with rheumatic diseases.Patients and methodsWe evaluated the presence of ADAs in 248 patients with inflammatory rheumatic diseases after 6 months of treatment with anti-TNF drugs: 26 patients were treated with infliximab (IFX; three with rheumatoid arthritis [RA], 13 with ankylosing spondylitis [AS], 10 with psoriatic arthritis [PsA]); 83 treated with adalimumab (ADA; 24 with RA, 36 with AS, 23 with PsA); 88 treated with etanercept (ETA; 35 with RA, 27 with AS, 26 with PsA); 32 treated with certolizumab (CERT; 25 with RA, two with AS, five with PsA); and 19 treated with golimumab (GOL; three with RA, seven with AS, nine with PsA). Serum drug and ADA levels were determined using Lisa-Tracker Duo, the ADA-positive samples underwent an inhibition test, and the true-positive samples underwent genetic HLA typing. To have a homogeneous control population, we also performed genetic HLA typing of 11 ADA-negative patients.ResultsAfter inhibition test, the frequency of ADAs was 2/26 patients treated with IFX (7.69%), 4/83 treated with ADA (4.81%), 0/88 treated with ETA (0%), 4/32 treated with CERT (12.5%), and 1/19 treated with GOL (5.26%). The frequency of HLA alleles in the examined patients was HLA-DRβ-11 0.636, HLA-DQ-03 0.636, and HLA-DQ-05 0.727. The estimated relative risks between the ADA-positive patients and the ADA-negative patients were HLA-DRβ-11 2.528 (95% CI 0.336–19.036), HLA-DQ-03 1.750 (95% CI 0.289–10.581), and HLA-DQ-05 2.424 (95% CI 0.308–15.449).ConclusionThis is the first study that shows an association between HLA and genetic factors associated with the occurrence of ADAs in patients with rheumatic diseases, but the number of samples is too small to draw any definite conclusion.

O50 High Frequency of Anti-Drug Antibodies and Correlation of Low Random Drug Levels with Lack of Efficacy in Certolizumab Pegol-Treated Patients with Rheumatoid Arthritis

O50 High Frequency of Anti-Drug Antibodies and Correlation of Low Random Drug Levels with Lack of Efficacy in Certolizumab Pegol-Treated Patients with Rheumatoid Arthritis

A Phase 2, Non-Comparative, Open-Label, International Study of MEDI4736 in Patients with Locally Advanced or Metastatic PD-L1-Positive NSCLC (Stage IIIB-IV) Who have Received ≥ 2 Prior Systemic Treatment Regimens (Atlantic)

ABSTRACT Background The inhibitory programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway plays a major role in controlling T cell activation and is utilised by tumour cells to evade antitumour responses. Anti-PD-L1 monoclonal antibodies (mAbs) have shown encouraging preclinical and clinical activity against a number of tumour types. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 and is associated with a low frequency of anti-drug antibodies. Clinical activity for MEDI4736 in non-small cell lung cancer (NSCLC) has been observed in a Phase 1 study, with preliminary evidence indicating that PD-L1 expression is associated with a higher objective response. Here we describe an ongoing study to assess the efficacy and safety of MEDI4736 in patients with locally advanced or metastatic NSCLC. Trial design ATLANTIC (NCT02087423) is a phase 2, non-comparative, multicentre, international, open-label study, evaluating the efficacy and safety of MEDI4736 (10 mg/kg administered intravenously every 2 weeks for up to 12 months) in patients with PD-L1-positive locally advanced or metastatic NSCLC (Stage IIIb – IV). Eligible patients will have a WHO Performance Status of 0 or 1, and must have received at least 2 prior systemic treatment regimens, including a platinum-based chemotherapy regimen. Approximately 188 patients (∼50% known epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] positive [Cohort 1] and ∼50% EGFR and ALK-negative [Cohort 2]), will be treated at ∼100 sites across North America, Asia, and Europe. Prior therapy for Cohort 1 patients must include the appropriate tyrosine kinase inhibitor. The primary outcome measure is objective response rate according to RECIST 1.1. Secondary outcome measures will further assess efficacy (including disease control rate, duration of response, deep sustained response, progression-free survival and overall survival), safety, tolerability, pharmacokinetics, and immunogenicity of MEDI4736. Recruitment is ongoing. This abstract was accepted and previously presented at ESMO 2014, Annals of Oncology, Volume 25, Supplement 4, 1335TiP. Disclosure N. Rizvi: I receive consulting income from MedImmune, Roche, Merck and BMS; M. Ballas: Employee of AstraZeneca and owns stock/stock options in AstraZeneca. Owns stock in Bristol Myers Squibb; D. Jayawardene and P.K. Stockman: Employee of AstraZeneca and owns stock/stock options in AstraZeneca; J.D. Powderly: Employment, Human Application Lab. Consultancy, BMS, Genentech, Amplimmune, Merck. Honoraria, BMS. Research funding, BMS, Genentech, Amplimmune, Merck, Astrazeneca, Imclone/Lilly. Speaker Bureau and Advisory Board BMS.

A Phase 2, Non-Comparative, Open-Label, Multicenter, International Study of Medi4736 in Patients with Locally Advanced or Metastatic Pd-L1-Positive Nsclc (Stage Iiib-Iv) Who Have Received ≥ 2 Prior Systemic Treatment Regimens, Including a Platinum-Based Chemotherapy (Atlantic)

ABSTRACT Background: Programmed cell death-ligand 1 (PD-L1) is a cell surface protein that delivers inhibitory signals to T cells through interaction with the programmed cell death-1 (PD-1) receptor and the CD80 receptor. Numerous cancers appear to exploit this PD-L1/PD-1 pathway and evade the immune system via upregulation and cell surface expression of PD-L1. Anti-PD-L1 monoclonal antibodies (mAbs) have shown encouraging preclinical and clinical activity against a number of tumor types. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 and is associated with a low frequency of anti-drug antibodies. Evidence of clinical activity for MEDI4736 in NSCLC has been observed in a Phase 1 study. The current Phase 2 study assesses the efficacy and safety of MEDI4736 treatment in patients with locally advanced or metastatic NSCLC. Trial design: ATLANTIC (NCT02087423) is a Phase 2, non-comparative, multicenter, international, open-label study, evaluating the efficacy and safety of MEDI4736 (administered IV every 2 weeks for up to 12 months) in patients with PD-L1-positive locally advanced or metastatic NSCLC (stage IIIb - IV). Eligible patients (age ≥18 years) will have a WHO Performance Status of 0 or 1 and must have received at least 2 prior systemic treatment regimens, including a platinum-based chemotherapy regimen. Approximately 188 PD-L1-positive patients (∼50% known EGFR or ALK positive [Cohort 1] and ∼50% EGFR and ALK-negative [Cohort 2]), will be treated at ∼100 sites across North America, Asia, and Europe. Prior therapy for Cohort 1 patients must include appropriate tyrosine kinase inhibitor. The primary outcome measure is objective response rate according to RECIST 1.1. Secondary outcome measures will further assess efficacy (including disease control rate, duration of response, deep sustained response, progression-free survival and overall survival), safety, tolerability, pharmacokinetics, and immunogenicity of MEDI4736. Recruitment is ongoing. Disclosure: N. Rizvi: I receive consulting income from Medimmune, Roche, Merck and BMS; J. Gray: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; M. Ballas: Employee of AstraZeneca and owns stock/stock options in AstraZeneca; D. Jayawardene: Employee of AstraZeneca and owns stock/stock options in AstraZeneca; P. Stockman: Employee of AstraZeneca and owns stock/stock options in AstraZeneca; J.D. Powderly: Speaker Bureaus BMS: Ipilimumab & ImmunoOncology. Dendreon: Sipileucel T. Genentech: Bevacizumab. Research Funding: BMS, Genentech/Roche, AstraZeneca/MedImmune, Merck/EMD Serono, Amplimmune, CellDex, ABBVie, Lilly/Imclone. Stock Ownership: BioCytics

Phase 1 Study Evaluating Safety and Tolerability of Medi4736, an Anti-Programmed Cell Death Ligand-1 (Pd-L1) Antibody, in Combination with Dabrafenib and Trametinib or Trametinib Alone in Patients with Unresectable or Metastatic Melanoma

ABSTRACT Background: Targeted treatments have significantly improved outcomes in patients (pts) with metastatic melanoma (MM). The combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, provides high response rates in BRAF mutation-positive melanoma (BRAF V600E/K melanoma). Trametinib has also shown clinical activity in BRAF wild-type (WT) melanoma. The addition of an immunomodulator may further improve clinical outcomes in metastatic melanoma pts. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 and is associated with a low frequency of anti-drug antibodies, showed durable clinical activity in a Phase 1 study of pts with solid tumors including melanoma. MEDI4736 is being evaluated in combination with dabrafenib/trametinib or trametinib alone in BRAF mutation-positive or BRAF mutation-negative melanoma. Trial design: This global multicenter, open-label Phase 1b study (NCT02027961) is enrolling adults with unresectable or MM and ECOG performance status 0–1 into 3 cohorts. In cohort A, BRAF-V600E/K melanoma pts receive dabrafenib orally (PO) twice daily, trametinib PO once daily (QD) and MEDI4736 intravenously (IV) every 2 wks (q2w), given concomitantly followed by continued dabrafenib/trametinib until progressive disease (PD). In cohorts B and C, BRAF mutation-negative (BRAF-WT) pts receive trametinib PO QD and MEDI4736 IV q2w according to 2 different treatment schedules,until PD. Primary objectives are determination of maximum tolerated dose (dose-limiting toxicity) and safety profile (adverse events, laboratory evaluations, physical exams, echocardiograms/electrocardiograms) of MEDI4736 in combination with dabrafenib/trametinib or trametinib alone. Secondary objectives include antitumor activity (objective response based on RECIST, duration of response, PFS, and overall survival), pharmacokinetic profile, and immunogenicity of the combination. Exploratory objectives include biomarkers, patient-reported outcomes, and tumor growth parameters. Recruitment is ongoing (target: 69 pts). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting Chicago, June 2014 (TPS9108). Disclosure: M.S. Gordon and D. Lawrence: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; J. Lutzky: Medimmune/Astra-Zeneca: clinical trial support. Genentech, BMS, Prometheus: both clinical trial support and speaker bureau. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; M. Butler: Financial support from MedImmune to cover the costs of conducting sponsored clinical studies of Medi4736. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; P.A. Ascierto: Consultancy/research funding/honoraria: BMS, Roche-Genentech, Merck Sharp & Dohme, GSK, Ventana, and Novartis. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; B. Hug: Employee of GlaxoSmithKline. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins, A. Di Pietro, X. Li and P.B. Robbins: Employee of MedImmune and owns stock/stock options in AstraZeneca; A. Ribas: Consultant/funding/stock options Amgen Daiichi-Sankyo GSK Genentech-Roche Merck Novartis Pierre-Favre Kite Pharma Flexus. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.

Abstract 4334: Identification and elimination of T-cell epitopes in recombinant immunotoxins used to treat cancer.

Abstract Moxetumomab pasudotox and SS1P are immunotoxins that have been developed in our lab to treat cancer. Moxetumomab pasudotox, which can be given for many treatment cycles, targets CD22 and has produced many complete remissions in drug-resistant hairy cell leukemia. However, SS1P, which targets mesothelin, could only be given for one cycle before ADA (anti drug antibodies) developed and neutralized the protein. We hypothesize that SS1P could be more effective if it were less immunogenic and more treatment cycles could be given. To de-immunize the immunotoxin we sought to identify and remove T cell epitopes. To identify the epitopes we stimulated PBMCs from 50 normal donors with whole immunotoxin for 14 days to expand the T cells and then stimulated the T cells with peptides (15 mers) derived from the toxin, followed by ELISpot to identify the peptides that stimulated the T cells. We found that all 50 donors gave a positive response, which correlates with the frequency of ADAs in patients with normal immune systems. We used alanine-scanning mutagenesis to determine which amino acids in each peptide are important for T cell stimulation. SS1P contains domains II and III of PE. In 46% of the donors we found a single highly immunodominant and promiscuous epitope that is located in domain II. We previously showed we could eliminate almost all of domain II while retaining excellent cytotoxic activity. These data indicate that immunogenicity should be eliminated in 34% of normal individuals donors and diminished in another 42% by deletion of domain II. In domain III we identified 5 peptides that stimulated T cell responses in different donors and also identified alanine mutations within each peptide that eliminated or greatly lowered T cell stimulation in most donors. We are using this information to make immunotoxins with mutations in domain III that should have a further decrease in immunogenicity. We have shown that among many individuals with different HLA alleles there is a dominant T cell epitope in domain II of PE38 and 5 subdominant epitopes in domain III. We plan to use this information to make new immunotoxins in which the large majority of T cell epitopes are silenced resulting in diminished immunogenicity of the immunotoxin. We plan to combine these T cell mutations with B cell mutations previously described to make immunotoxins with very low immunogenicity allowing more treatment cycles to be given and better anti-tumor activity achieved. Citation Format: Ronit Mazor, Aaron N. Vassall, Jaime A. Eberle, Richard Beers, Xiaobo Hu, Itai Benhar, Ira Pastan. Identification and elimination of T-cell epitopes in recombinant immunotoxins used to treat cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4334. doi:10.1158/1538-7445.AM2013-4334