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
基本信息
- 批准号:10547573
- 负责人:
- 金额:$ 30.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffinityAmino AcidsAntibodiesAntibody ResponseAntigen-Presenting CellsApoptosisArthritisBindingBiologicalBiological AssayBiological ProductsBiophysicsBlood CirculationCell Culture TechniquesCell LineCharacteristicsChronicChronic DiseaseClinicalColitisColonCrohn&aposs diseaseCultured CellsCyclic Amino AcidsCyclic PeptidesDevelopmentDigestionDiseaseDoseDrug KineticsEnzymesEpithelial CellsExhibitsExposure toFecesFundingGastrointestinal tract structureGoalsGoldHigh Pressure Liquid ChromatographyHistocytochemistryHospitalizationHumanHumiraImageImmune responseImmunosuppressionInfectionInflammationInflammatoryInflammatory Bowel DiseasesInjectionsIntellectual PropertyIntestinesKnock-inLeadLigandsLiquid substanceMediatingMembraneMethodologyMethodsModelingMonitorMonoclonal AntibodiesMorbidity - disease rateMucous MembraneMusOpportunistic InfectionsOralOral AdministrationOutcomePatientsPenetrationPeptide HydrolasesPeptidesPermeabilityPersonsPhage DisplayPharmaceutical PreparationsPhasePhase I Clinical TrialsPlasmaPopulationPrevalencePropertyProteolysisPsoriasisRattusResistanceRiskSiteSmall Business Innovation Research GrantSolubilitySpecificityStomachSurface Plasmon ResonanceTNF geneTherapeuticTissuesToxic effectToxicologyTransgenic MiceUlcerative ColitisUrineUveitisabsorptionadalimumabanalytical methodantigen processingbasebiophysical propertiescell killingchemically induced colitisdesigndisabilityeffective therapyenantiomerexperienceexperimental studygastrointestinalileumimmunogenicimmunogenicityimmunoregulationin vitro Assayin vivoin vivo Modelinhibitorinnovationjejunumnonhuman primatenovel therapeuticsparenteral administrationpeptide Lreceptor bindingrisk benefit ratioside effectsmall moleculesystemic toxicitytherapeutic candidatetumor necrosis factor-alpha inhibitor
项目摘要
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
项目成果
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