HCO ANTIBODY, INC. — Department of Health and Human Services SBIR Phase I: NIAID

Description

Abstract Ulcerative ColitisUCand Crohn s DiseaseCDare the two most common Inflammatory Bowel DiseasesIBDinvolving excessive and chronic inflammation of the gastro intestinal tractCurrentlystandard of care includes aminosalicylatescorticosteroidsgeneral immunosuppressants and antibiotics with the aim to induce and maintain remissionsIf remission cannot be achieved or the disease is too severebiologics are administeredNeverthelessroughlyof patients go into remission after treatment with biologicsand roughlyof these patients stop responding to therapiesindicating that numerous patients need alternatives to current therapiesNicotinamide adenine dinucleotideNADis one of the key coenzymes regulating many metabolic pathwaysCDis a NAD degrading ectoenzyme that plays a major role in NAD metabolismIn animal models CDmodulates immune responses of T cellsmacrophages and neutrophilsThese models support the hypothesis that colonic inflammation leads to a decrease in NAD levels of intestinal cellsSubsequent NAD decline would decrease the activity of anti inflammatory NAD dependent deacetylasesCurrent mAbs against CDkill CDcells and have been shown to be effective treatments of Multiple MyelomaHoweverfor auto immune patientsremoval of CDcellsincluding suppressive immune cellscould lead to exacerbation of diseaseWe will use our fully human heavy chain only antibodiesUniAbsto create multivalent biparatopic molecules that solely block CDhydrolase activitiesOur custom TeneoSeek discovery pipeline enables effective UniAbs screens by applying high throughput functional assaysUniAbs will be expressed on silenced IgG backgrounds to eliminate immune effector functionsPreliminary resultsusing an in house UniAb specific for mouse CDhydrolaseindicate that inhibition of CDhydrolase leads to higher intracellular NAD levels in in vivo mouse models and better clinical scores in DSS modelwidely used IBD model in miceSpecific AimIdentification and characterization of high affinity blockers of human CDhydrolase activitiesWe will immunize our UniRats with recombinant human CDproteins with the goal to identify at leastUniAb sequence families with potent hydrolase blocking activitiesTwo sequence families will be selected that do not compete for binding to CDSpecific AimDevelopment of human bivalent and tetravalent high affinity UniAbsCombinations of VH domains selected in SAwill be expressed as bivalent and tetravalent UniAbsWe will produceg of each hydrolase blocker for future animal studiesIn phase IIpre clinical studies will be performed on selected UniAbs to enable the filing of an INDThese studies will include tox and PK PD studies in monkeys and miceProof of principle provided by this work will support development of the same product for other inflammatory diseases such as rheumatoid arthritis and asthma Narrative Ulcerative ColitisUCand Crohn s DiseaseCDare the two most common forms of Inflammatory Bowel DiseaseIBDCurrent standard of care of these auto immune diseases is insufficient for many patientsRoughlyof patients either do not respond to powerful biologics or stop respondingWe will develop a fully human antibody with small binding sites uniquely well suited for the inhibition of a key enzyme involved in IBD progression