Phase II year
2019
(last award dollars: 2020)
Phase II Amount
$1,582,190
Biologics are increasingly used in the treatment of autoimmune and inflammatory diseases. Monoclonal antibody (mAb) drugs that target tumor necrosis factor alpha (TNF-a), such as Remicade (infliximab), are blockbuster drugsglobal sales of infliximab were close to $6B in 2016. However, post-approval studies have revealed inefficiencies in the use of these anti-TNF-a biologics; some patients do not respond to mAb therapies upon induction, whereas others lose response over time. Primary causes of dosing inefficiency include a rigid dosing schedule and the frequent development of anti-drug antibody (ADA) responses in treated patients. The clinical data strongly point to the need for therapeutic dose monitoring of mAb drugs to ensure an optimal therapeutic window in every patient. While laboratory-based test methods are available, there are no point-of-care tests for measuring the concentration of either infliximab or ADAs. The goal of this project is to develop lateral flow immunoassays (LFAs) for rapid measurement of free infliximab and ADA levels in finger-stick blood samples. Our proprietary technology uses small peptide mimetics (Veritopes) of the antigen as a specific capture reagent. Our tests are based on ligand-binding activity, and are thus expected to detect the parent mAb drug (infliximab), as well as new biosimilars (infliximab-dyyb, infliximab-abda). We previously qualified the technical feasibility of Veritope-based LFAs for the detection of rituximab concentration in patient serum. The objectives of this project are to: 1) generate Veritope specific for infliximab and implement the peptide in a LFA for the measurement of free infliximab levels in blood at the point-of-care, 2) Demonstrate ADA detection for infliximab using a complement point-of-care LFA that incorporates an initial acid dissociation step, and 3) validate free drug and ADA LFA using patient samples. These innovative products will fulfill of an unmet clinical need for a rapid, cost effective, and accurate dose monitoring assay. Precision dosing through data-driven, personalized regimens will improve treatment outcomes and maximize the efficient use of infliximab.
Public Health Relevance Statement: Project narrative: Infliximab is a monoclonal antibody used to treat Crohns disease and ulcerative colitis, but there is growing evidence that some patients are not receiving a therapeutic dose of this agent when given standard doses. This project will finalize development and fully validate simple lateral flow assay devices that can measure within minutes how much infliximab is present in a patients blood.
NIH Spending Category: Autoimmune Disease; Biotechnology; Clinical Research; Digestive Diseases; Immunization; Immunotherapy; Inflammatory Bowel Disease
Project Terms: Acids; Acute; Antibodies; Antibody Response; Antibody-drug conjugates; antigen binding; Antigens; Autoimmune Diseases; Autoimmune Process; base; Bedside Testings; Biological; Biological Assay; Biological Response Modifier Therapy; Biological Sciences; Blood; Blood drug level result; Blood specimen; Body Surface Area; Body Weight; Cells; Clinical; Clinical Data; Clinical Research; clinically relevant; Collaborations; Complement; Conjugating Agent; cost effective; Crohn's disease; Data; Detection; Development; Device or Instrument Development; Devices; Disease; Dissociation; dosage; Dose; Drops; drug efficacy; Drug Kinetics; Drug Targeting; Enrollment; Ensure; Enzyme-Linked Immunosorbent Assay; expectation; experience; Fab Immunoglobulins; Failure; Fingers; Future; Goals; Gold Colloid; Health; Immune response; Immune system; Immunoassay; improved; Individual; Inflammatory; infliximab; innovation; Label; Laboratories; Lateral; Lead; Ligand Binding; Link; Malignant Neoplasms; Measurement; Measures; meetings; Membrane; Methods; Monitor; Monoclonal Antibodies; Monoclonal Antibody Therapy; novel; Observational Study; Parents; Patients; Peptides; peptidomimetics; Performance; performance tests; Pharmaceutical Preparations; Phase; Physiological; point of care; Population; portability; primary endpoint; Production; Protocols documentation; Quality Control; Reagent; recruit; Regimen; Reporting; response; rituximab; Sales; Sampling; Schedule; Sensitivity and Specificity; Serum; side effect; Specificity; Structure; Technology; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Time; TNF gene; treatment choice; Treatment outcome; Ulcerative Colitis; Universities; Validation; Work
