A Next-Generation Therapeutic for Treatment of TNFα-mediated Inflammatory Diseases

治疗 TNFα 介导的炎症性疾病的下一代疗法

• 批准号: 10547573
• 负责人: ALAN F WAHL
• 金额: $ 30.15万
• 依托单位: D BIOTHERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547573
• 关键词: Affinity; Amino Acids; Antibodies; Antibody Response; Antigen-Presenting Cells; Apoptosis; Arthritis; Binding; Biological; Biological Assay; Biological Products; Biophysics; Blood Circulation; Cell Culture Techniques; Cell Line; Characteristics; Chronic; Chronic Disease; Clinical; Colitis; Colon; Crohn' s disease; Cultured Cells; Cyclic Amino Acids; Cyclic Peptides; Development; Digestion; Disease; Dose; Drug Kinetics; Enzymes; Epithelial Cells; Exhibits; Exposure to; Feces; Funding; Gastrointestinal tract structure; Goals; Gold; High Pressure Liquid Chromatography; Histocytochemistry; Hospitalization; Human; Humira; Image; Immune response; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injections; Intellectual Property; Intestines; Knock-in; Lead; Ligands; Liquid substance; Mediating; Membrane; Methodology; Methods; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mucous Membrane; Mus; Opportunistic Infections; Oral; Oral Administration; Outcome; Patients; Penetration; Peptide Hydrolases; Peptides; Permeability; Persons; Phage Display; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plasma; Population; Prevalence; Property; Proteolysis; Psoriasis; Rattus; Resistance; Risk; Site; Small Business Innovation Research Grant; Solubility; Specificity; Stomach; Surface Plasmon Resonance; TNF gene; Therapeutic; Tissues; Toxic effect; Toxicology; Transgenic Mice; Ulcerative Colitis; Urine; Uveitis; absorption; adalimumab; analytical method; antigen processing; base; biophysical properties; cell killing; chemically induced colitis; design; disability; effective therapy; enantiomer; experience; experimental study; gastrointestinal; ileum; immunogenic; immunogenicity; immunoregulation; in vitro Assay; in vivo; in vivo Model; inhibitor; innovation; jejunum; nonhuman primate; novel therapeutics; parenteral administration; peptide L; receptor binding; risk benefit ratio; side effect; small molecule; systemic toxicity; therapeutic candidate; tumor necrosis factor-alpha inhibitor

PROJECT SUMMARY Inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) are debilitating disorders that afflict ~1.3% of the U.S. population. Blockade of TNFα-driven inflammation with approved anti-TNFα biologics has been an effective IBD treatment for many patients. However, loss of efficacy due to anti-drug antibodies (ADAs) and toxicities such as serious infections often lead to discontinuation of anti-TNFα biologics. We have developed a stable, protease-resistant, anti-TNFα D-peptide, DBT178, that is designed to be taken orally and delivered intact to gastrointestinal (GI) sites of inflammation characteristic of IBD. Other therapeutic candidates evaluated by other sponsors have already demonstrated proof of activity for orally administered anti- TNFα biologics in IBD patients. However, these agents have not been feasible as oral IBD therapeutics primarily due to high dosing requirements resulting from low potency and sensitivity to GI proteases. DBT178 is an ~8 kDa highly potent and specific anti-TNFα D-peptide that was discovered via mirror-image phage display. Multiple in vitro assays have demonstrated that DBT178 is substantially more potent than adalimumab (Humira®) antibody at blocking TNFα ligand:receptor binding and TNFα-mediated cell killing. Unlike natural peptides composed of L-amino acids, D-peptides are composed of mirror-image D-amino acids and are the enantiomers of their natural counterparts. Proteolytic enzymes, including those found in the gut, are known to exhibit chiral specificity, thus D-peptides demonstrate remarkable stability to proteases. In rats, when administered by oral gavage, a “model” D-peptide closely related to DBT178 was excreted intact in stool and was not absorbed into systemic circulation. Therefore, we hypothesize that orally administered DBT178 will inhibit TNFα -induced mucosal and submucosal inflammation characteristic of IBD without associated absorption into the portal circulation, systemic distribution, or systemic immunosuppression. Furthermore, D-peptides are also minimally immunogenic since they are resistant to the proteolytic antigen processing carried out by antigen presenting cells that is necessary for successful immune responses. Expected gut restriction and low immunogenicity suggest that DBT178 is unlikely to induce anti-drug antibodies (ADA) or the associated loss of efficacy observed in ~30% of IBD patients treated with current anti-TNFα biologics. DBT178 is a promising product candidate with the potential to disrupt the multi-billion-dollar anti-TNFα therapeutics landscape for treatment of psoriasis, inflammatory forms of arthritis, uveitis and IBD. For this application we have focused on its potential to provide a convenient, gut restricted and non-immunogenic oral alternative to the currently approved anti-TNFα parenteral biologics. In this proposal, we request funding to manufacture and formulate a non-GMP batch of DBT178, characterize its stability and activity in simulated gastric and intestinal fluids, and assess its pharmacokinetics and GI tissue penetration when given orally to mice. We will also characterize its immunogenicity in non-human primates.

项目总结